Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall

Hypertension Induced Morphological and Physiological Changes in Cells of the Arterial Wall Abstract Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted. blood pressure; cell types, hypertension, vascular, vessel wall According to the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults by the American Heart Association and American College of Cardiology, 130/80 mm Hg rather than 140/90 mm Hg is considered elevated arterial blood pressure, and approximately, half of the United States adult population meet this criteria.1 As the United States population ages, the number of patients diagnosed with hypertension will continue to increase. The 2017 guideline reflects the recognition that arterial blood pressure measurements thought to be prehypertensive, correlate with pathophysiological changes in the cardiovascular system, and increase a patient’s risk for hypertension-associated comorbidities, including stroke and death. This new guideline highlights the importance of early identification and increased patient monitoring to prevent hypertension-related side effects. Hypertension is associated with vascular dysfunction, with changes are seen at the histological and cellular level in vessels from hypertensive animals and human patients. This mini-review reflects studies from both animal and human subjects, the majority which has been performed in animal models of hypertension. Regardless of the model subject, it is highly debated whether pathophysiological changes are one of the causes of elevated blood pressure or the effect of chronic hypertension. The current literature focuses mostly on the changes in morphology and function of endothelial and vascular smooth muscle cells (VSMCs). However, because vascular dysfunction in hypertension implicates other vascular cells, such as fibrocytes, pericytes, and even cells of the perivascular adipose tissue (PVAT), in this mini-review, we have focused our discussion on these nonendothelium vascular cell types. TUNICA INTIMA Endothelial cells The endothelium is the major interface between the vascular wall and blood and therefore is an important organ in the regulation of vascular tone and hemostasis. Despite only being a thin monolayer, the endothelium is a dynamic organ sensitive to physical forces2 exerted by the flowing blood (shear stress) and chemical signals3 that affect vascular tone, cell adhesion, platelet function, VSMC phenotype, and vessel wall inflammation. Broadly, the endothelium has 3 major functions—secretion, physical barrier properties, and metabolism—each of which changes in hypertension. The most well-known function of the endothelium is its ability to secrete vasoactive molecules (see Table 1 for a summary of vasoactive molecules involved in hypertension and released by the vessel wall cells). In healthy conditions, the endothelium regulates the abundance of diffusible vasodilatory/anticoagulatory factors that hyperpolarize the underlying vascular smooth muscle to maintain appropriate blood flow. In hypertension, there is a shift in the balance of these factors. Generally, the endothelium from both hypertensive animals and patients increases its secretion of procontractile factors and decreases its secretion of prorelaxant factors. However, there are instances where vasodilatory factors are elevated in hypertension,4 likely as a compensatory mechanism during the development phase of high blood pressure. It has also been acknowledged that endothelium-derived hyperpolarization could occur through intercellular coupling and therefore be considered a solely electrical event. There is ongoing discovery of novel vasoactive molecules that are secreted from the endothelium and directly impact vascular tone or indirectly modulate the abundance of traditional vasoactive molecules (e.g., nitric oxide bioavailability, prostaglandin synthesis). Damage-associated molecular patterns, cell components released or secreted during cell death, have emerged as novel mediators5 and modulators6 of endothelial function, acting in an autocrine, paracrine, and endocrine fashion. Table 1. Vasoactive molecules released by cells of the vessel wall during hypertension Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Abbreviations: DAMP, damage-associated molecular pattern; EDHF, endothelium-derived hyperpolarizing factor; IL, interleukin; NO, nitric oxide; PVAT, perivascular adipose tissue; TGF, transforming growth factor; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell; ?, unknown effect. View Large Table 1. Vasoactive molecules released by cells of the vessel wall during hypertension Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Abbreviations: DAMP, damage-associated molecular pattern; EDHF, endothelium-derived hyperpolarizing factor; IL, interleukin; NO, nitric oxide; PVAT, perivascular adipose tissue; TGF, transforming growth factor; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell; ?, unknown effect. View Large Endothelial cells are linked to one another via junctional structures forming a barrier. In hypertension, this barrier function is impaired, and the permeability of the endothelium increases. Endothelium dysfunction diminishes the protection of end organs and allows for increased passage of solutes and immune cells from the bloodstream, causing increased edema and inflammation.7 Prohypertensive factors contribute to endothelial barrier dysfunction. For example, angiotensin-II (Ang-II) disrupts the blood–brain barrier in spontaneously hypertensive rats (SHR),8 and aldosterone can diminish endothelial nitric oxide synthase activity via rearrangement of the actin cytoskeleton.9 Furthermore, as RhoA is generally considered the master regulator of actin cytoskeleton formation,10 an improvement in endothelial barrier function could be another mechanism of how RhoA/ROCK inhibition (e.g., fasudil) acts as an antihypertensive therapy.11 Similar to vasoactive molecules, novel mediators of endothelial permeability and actin cytoskeleton dynamics are emerging.12,13 Whether these novel factors contribute to the pathogenesis of hypertension is currently an unexplored area of research. Finally, the endothelium can also function as a metabolic unit, with a host of proteolytic enzymes and transporters that take up and process circulating molecules. The endothelium can clear prohypertensive molecules such as low-density lipoprotein,14 prostaglandins,15 and endothelin-1.16 In hypertension, however, the metabolism of endothelial cells becomes dysfunctional promoting a procontractile, proinflammatory, and pro-oxidative milieu. For example, uptake of the above mentioned prohypertensive molecules, as well as their destruction into inactive metabolites (e.g., serotonin) is impaired.17,18 In summary, it is well established that the secretory, barrier, and metabolic function of the endothelium becomes ineffective at maintaining the necessary degree of vascular homeostasis, and this promotes the development and maintenance of hypertension. However, still being revealed are multiple and intertwining mechanisms underlying the endothelium dysfunction, beyond high blood pressure itself, as well as the multiple ways that the endothelium can exert autocrine, paracrine, and endocrine influences on itself and the other organs involved in the etiology of hypertension. Interstitial cells of Cajal The interstitial cells of Cajal are a subpopulation of cells found in tissues containing smooth muscle. They are irregular in shape, contain thin processes, and are noncontractile.19 The presence and function of interstitial cells within the vasculature have not been greatly characterized. The location of these cells varies depending on tissue type, ranging from the subendothelial layer to the media-adventitia border of veins (portal, pulmonary, postcaval) and arteries (mesenteric, cerebral, aortic, carotid).20–26 Interstitial cells of Cajal exhibit pacemaker activity within veins, whereas their function in arteries is less clear. Some evidence suggests these cells have roles in angiogenesis, intercellular communication, and vessel maintenance.27 Knowledge on the role of vascular interstitial cells of Cajal in hypertension is greatly lacking, which may be a consequence of the inconsistency in nomenclature and/or lack of biomarkers. However, one study demonstrated that hypertension induced partial loss and rupture of these cells, and this was associated with a disturbance in intestinal smooth muscle cell contraction.28 Therefore, it is reasonable to hypothesize that functional and structural changes within the vascular interstitial cells of Cajal may play a role in the development and/or maintenance of hypertension. TUNICA MEDIA Vascular smooth muscle cells Total peripheral resistance is defined by Poiseuille’s law, in which 3 factors are the primary determinants of the resistance to blood flow within a vessel: lumen diameter, vessel length, and viscosity of the blood. The most significant is the lumen diameter, given that vessel resistance is inversely proportional to the radius to the fourth power (r4). Therefore, a 50% reduction in radius should increase resistance 16-fold. Adjustments in total peripheral resistance are directly determined by alterations in the morphology and/or function of VSMCs. Under physiological conditions, VSMCs are embedded in a network of elastin-rich extracellular matrix and the basement membrane, which surrounds each VSMCs and separates the VSMCs-containing medial cell layer from the endothelium.29 The basement membrane acts as a barrier to VSMCs migration, proliferation, and hypertrophy. VSMCs structural changes in hypertension are collectively termed vascular remodeling. It is observed when there is a change in diameter of a fully relaxed vessel that is not explained by a change in transmural pressure or compliance and thus is structural in nature.30 Vascular remodeling is classified as hypertrophic, eutrophic, or hypotrophic. Furthermore, remodeling can be inward (reduced luminal diameter) (Figure 1) or outward (increased luminal diameter).31,32 In hypertension, increased peripheral resistance associated to structural changes (remodeling) of the vasculature was proposed in the 1950s by Folkow.33 The most common type in hypertension is inward remodeling, causing a reduction of the luminal diameter under passive conditions. Outward remodeling is generally seen during antihypertensive treatment and in conditions of increased flow.31 In inward eutrophic remodeling, wall cross-sectional area will be preserved by repositioning of the VSMCs, which normalizes the circumferential stress of the resistance vessel exposed to increased blood pressure. It is suggested that the inward eutrophic remodeling precedes and prevents hypertrophy if the rearrangement effectively normalizes the circumferential stress. However, if the rearrangement does not occur, VSMCs are stimulated and the cross-sectional area is injured.34 These structural changes increase the wall-to-lumen ratio which causes an increase in the peripheral resistance. Figure 1. View largeDownload slide Arterial remodeling in hypertension. Typical representative images of mesenteric resistance arteries from Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) showing the inward remodeling in SHR arteries. Confocal images (×40 magnification) of increased colocalization immunofluorescence for Toll-like receptor 9 (red) and MyD88 (green). Figure 1. View largeDownload slide Arterial remodeling in hypertension. Typical representative images of mesenteric resistance arteries from Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) showing the inward remodeling in SHR arteries. Confocal images (×40 magnification) of increased colocalization immunofluorescence for Toll-like receptor 9 (red) and MyD88 (green). Consistent findings demonstrate that during hypertension, VSMCs hyperplasia and hypertrophy represents 2 of the crucial anomalies responsible for the vascular inward remodeling and subsequent development of increased total peripheral resistance.30 Interestingly, the exaggerated response of VSMCs to growth factors in SHR persists in cell culture, indicating an intrinsic defect in hypertension-associated VSMCs hyperplasia and hypertrophy.35 For instance, many of the same factors that induce experimental hypertension also induce hypertrophy and hyperplasia in VSMCs, such as Ang-II, norepinephrine, and mineralocorticoids.30 Recent evidence has revealed that actin polymerization in VSMCs contributes to vascular remodeling. Accordingly, it has been observed that pressure-induced actin polymerization in VSMCs is one mechanism underlying myogenic behavior.36 Additionally, prolonged vasoconstriction of resistance arteries also involves VSMCs actin polymerization.37 For both the mechanotransduction pathway and agonist-induced changes in actin polymerization, RhoA-CdC42 pathway has been shown to be a primary contributor.38 Functionally, Ca2+ plays a central role of in the physiology and pathophysiology of VSMCs contractility. An increase in intracellular Ca2+ concentration is essential for activation of myosin light-chain kinase (MLCK), phosphorylation of MLC, myofilament cross-bridge cycling, and contraction. For instance, Ca2+ handling changes were found in human and experimental models of hypertension, including upregulation of receptor-operated and/or store-operated Ca2+ channels expression, upregulation or downregulation of L-type Ca2+ channels, increase in Ca2+ sensitization via RhoA activation, and increased mitochondria and sarcoplasmic reticulum Ca2+ stores.30 Therefore, disturbances in the handling of Ca2+ may be the most important factor unifying different mechanisms of VSMC dysfunctions in hypertension. Fibrocytes First described by Dr Bucala’s group in 1994 as a new leukocyte subpopulation exhibiting fibroblast-related properties, fibrocytes are considered one of the first cell lines physiologically responsible for wound repair and tissue regeneration.39,40 Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express stem cell (CD34), pan-hematopoietic (CD45), and monocyte markers (CD14 and 11) on their surface.40 Fibrocytes synthesize and release cytokines, metalloproteinases, and components of the connective tissue matrix (type I and III collagen, vimentin, and fibronectin), all of which contribute to tissue repair.41 The ability of fibrocytes to differentiate into fibroblasts or myofibroblasts, both responsible for collagen and proteoglycan production, further contributes to the tissue repair process.42 In physiological conditions, fibrocytes are not abundantly present in the arterial wall. However, in pathologic states, such as in hypertension,43,44 fibrocytes are recruited from the circulation through chemotactic ligand–receptor interactions to the injured tissue. During hypertension, resident fibrocyte hypertrophy and hyperplasia have also been described.45,46 Collagen accumulation and extracellular matrix reorganization, affected by resident fibrocytes, are also important factors that contribute to vessel wall stiffness and hypertension.43 In an experimental study of Ang-II-induced hypertension rodent model, fibrocytes played a pivotal role in the generation of vascular fibrosis through an increase in type I collagen production.44 Also, in pudendal arteries from SHR, an increase in fibrocyte markers was related to vascular dysfunction and erectile dysfunction.47 However, it is still controversial if circulating or resident fibrocytes play a major role in hypertension. For instance, little is known about how vascular resident fibrocytes contribute to the initial process of vascular remodeling. Furthermore, the suppressive effect of certain proinflammatory cytokines on fibrocyte formation and the role of this regulation in the development of vascular dysfunction is still not understood. TUNICA EXTERNA Fibroblasts Fibroblasts are the most abundant cell type within the tunica externa and key regulators of vascular wall structure and function.48 In vessels from normotensive rats, fibroblasts have a fusiform or polygonal morphology and have structural, secretory, and communicative (i.e., cell-to-cell interaction control) functions. Fibroblasts secrete growth factors, chemokines, and cytokines, which help control vascular function,49 elements of the extracellular matrix and aid in the degradation of extracellular matrix components. Fibroblasts are considered the principal cells for vascular remodeling in response to injury.50 However, during hypertension, fibroblasts undergo a morphological change that is accompanied with proliferation and migration into the tunica media.51 This response to injury also leads to the generation of chemokines, cytokines, adhesion molecules, reactive oxygen species, and matrix metalloproteinases (Table 1), along with proliferation of the vasa vasorum, eventually resulting in irreversible functional and structural remodeling of the vessel wall.48 Pericytes Pericytes are described as perivascular cells that “wrap” around arterioles, precapillary arterioles, capillaries, postcapillary venules, and venules52 (Figure 2). The ratio of pericytes to endothelial cells varies depending on which organ they are located in. Pericytes are found in greater numbers in areas of tight endothelial barrier regulation and slow endothelial proliferation. These cells exhibit a variety of roles that include scaffolding, communication, mechanical contractile force transmission, anchoring sites, and both the inability and ability to regulate vascular diameter in capillaries.53 Figure 2. View largeDownload slide Identification of pericytes in mice renal medullary capillaries. Pericytes (arrow) wrapping around medullary renal capillaries. Nerve/glial antigen 2-NG2 (red) used as pericyte localization marker for immunofluorescence. Abbreviation: DAPI (blue), 4′,6-diamidino-2-phenylindole. Figure 2. View largeDownload slide Identification of pericytes in mice renal medullary capillaries. Pericytes (arrow) wrapping around medullary renal capillaries. Nerve/glial antigen 2-NG2 (red) used as pericyte localization marker for immunofluorescence. Abbreviation: DAPI (blue), 4′,6-diamidino-2-phenylindole. Current literature suggests that not all pericytes are the same, as they exhibit different morphology and function; cell shape may range from a flat to a round cell body, and cell processes range from (i) wrapping entirely around a vessel, (ii) laying unidirectional in parallel with the length of the vessel, and (iii) exhibiting short processes creating a satellite-like cell shape.52 These differences can be categorized into 3 subclasses based on pericytes location along the capillary bed.52,54 Pericytes found closer to arterioles tend to exhibit circumferential processes that wrap around vessels.52,54 These pericytes have been reported to have more alpha-smooth muscle actin expression and have the ability to contract.52 Pericytes found around capillary beds tend to exhibit processes that run parallel to the vessel and express less alpha-smooth muscle actin than the pericytes found closer to arterioles. Pericytes found closer to venules have more of a satellite cell shape and do not express alpha-smooth muscle actin; therefore, they do not contract.54–58 The loose definition of pericytes and the contradictory role of this class of cells may account for varying reports of pericytes being both contractile and noncontractile.54,58,59 Hypertension has been associated with both an increase and a decrease in pericyte numbers.60–64 In mice with Ang-II-induced hypertension, the number of pericytes in cerebral arteries is decreased, leading to blood–brain barrier disruption.60 In contrast, SHR show increased pericyte number within the brain microcirculation, specifically within the motor cortex and pons.61 In pulmonary arterial hypertension, pulmonary arteries from both human and mice exhibit an increased number of pericytes with associated fibrosis and membrane thickening, and these where found to contribute to endothelial dysfunction.62–64 This phenomenon was suggested to be location specific and occur in response to recruitment signals to stabilize vessels. PERIVASCULAR ADIPOSE TISSUE In 1991, Cassis and Soltis65 used rat aorta from male Sprague-Dawley with and without PVAT to measure isometric force. Norepinephrine-induced contraction was reduced in tissues with PVAT. This experiment provided the first evidence that PVAT could change the function of the vessel around which it resided and possessed vasoactive functions. Since the publication of this seminal paper, scientists have discovered the importance of PVAT in modifying vessel function in multiple species, including humans, and in multiple vessel types, from large-sized vessels (aorta) to resistance-sized vessels. A majority of the work, however, has been done in larger size vessels such as the thoracic aorta because for these vessels, PVAT is easily identified. Current work has been reviewed by multiple investigators, and we encourage you to read these important reviews.66–75 PVAT is composed of multiple different cell types and tissues, including adipocytes, different cell types in the stromal vascular fraction, including small vasculature that supplies cells within PVAT with nutrients, fibroblasts and immune cells, and potentially nerves that innervate PVAT. Adipocytes can be both brown and white, and all arteries do not have the same “type” of PVAT. In fact, in the rat, the thoracic aorta is brown fat, the superior mesenteric artery is a mix of brown and white, and PVAT around the small mesenteric resistance arteries and veins is white. As such, no finding on a particular PVAT is necessarily applicable to another PVAT. Because there is no barrier between PVAT and the vessel, communication (cross-talk) can occur between PVAT and the vessel it surrounds. The PVAT anticontractile effects are caused by the release of different factors, including adiponectin, hydrogen sulfide, nitric oxide, etc.75 PVAT also has procontractile effects, caused by the production of vasoactive, contractile adipokines (such as angiotensin-II), and other small molecules (Table 1).76 Thus, it is the balance of molecules released from PVAT, as well as the bidirectional cross-talk,77 that ultimately determines the overall contributions made by PVAT to vessel contractility. The PVAT anticontractile action is lost in hypertension.68,69 The forms in which this anticontractile nature has been lost include both genetic and experimental models, as well as in humans with essential hypertension, though more work has been in done in animal models of obesity because of the increased burden of fat. Immune cell infiltration and PVAT PVAT appears to be a harbor for immune cells, both in healthy and pathologic states. This idea was led by the work of Tomas Guzik, who discovered that the presence of T cells was essential to the development of Ang-II-induced hypertension and hypertension-associated vascular dysfunction.78 Additionally, atheroprotective IgM-producing B cells were observed in the aortic PVAT of mice.79 Eosinophils may also be key in regulating the normal PVAT anticontractile function,80 and follicular dendritic cells emerge from precursors that exist in the perivascular space.81 Just recently, the importance of T cells in hypertension, as recruited to the PVAT, in both Ang-II and DOCA-salt hypertension in mice, was called into question with the inability of multiple labs across the country to reproduce the previously observed protection of the Rag1 mice (lack T and B cells) from Ang-II-induced hypertension.82 In dysfunctional PVAT (e.g., hypertension), immune cell infiltration becomes more prominent. Infiltrating cells include macrophages, memory T cells, IL-10-producing FoxP3 + T regulatory cells, natural killer cells, and granulocytes.83 Immune cell infiltrates in the PVAT contribute to the low-grade inflammation seen in multiple cardiovascular diseases.84–87 For instance, in humans, an increased burden of aortic PVAT in cardiovascular disease was seen in the Framingham Heart Study.88 Unfortunately, no PVAT-specific markers have been found that would permit PVAT-specific interventions. It would be ideal to have a biomarker or agent that could potentially turn a “sick” PVAT into a “healthy” PVAT. HYPERTENSION-RELATED CHANGES IN SPECIAL CIRCULATIONS Renal circulation The role that the kidney plays in the development and maintenance of hypertension has been described for centuries.89 The introduction of the pressure-natriuresis hypothesis by Arthur Guyton et al.90 in the 1970s suggested that a modification to the kidney’s capacity for water and sodium excretion was required for the perpetuation of chronic elevation of intra-arterial pressure, whereby the equilibrium point for salt and water excretion was shifted to a higher blood pressure. While this remains a largely accepted notion, some controversy arises with studies suggesting independent control of blood pressure by predominately neural and vascular mechanisms.91–93 The far reaching and complex role of renal physiology in blood pressure regulation is outside of the scope of this mini-review. However, hypertension is also recognized as one of the most important causes of end-stage renal disease,94 and the pathogenesis of hypertensive renal disease remains an area of great research interest and debate. Kidney damage is a prominent feature in most experimental models of hypertension.95–97 Many of the structural and functional changes in the vasculature recognized as hallmarks of chronic hypertension have also been observed in the kidney and warrant special consideration as components of this pathogenesis remain unclear. Specifically, renal injury in hypertension is heterogeneously distributed to the juxtamedullary region and outer medulla as has been observed in SHR, Dahl salt-sensitive hypertensive rats, renovascular hypertension, and Ang-II-induced hypertension.98–101 This results from the greater pressure gradient across the afferent arteriole in the juxtamedullary region, adjacent to the large arcuate artery, in contrast to the gradual pressure reduction that occurs over the length of the vasculature in the superficial cortical regions, including the entire interlobular artery and its afferent arterioles.98 A landmark study by Mori et al.101 supports the concept that elevated arterial pressure itself is primarily responsible for this renal injury. Mori et al. used the servocontrol method to maintain normotensive perfusion pressure to 1 kidney while inducing systemic hypertension via Ang-II infusion and showed extensive juxtamedullary, glomerular, and outer medullary tubulointerstitial injury in the pressure-uncontrolled kidney; this was largely prevented in the pressure-controlled contralateral kidney despite exposure to high levels of Ang-II. The exact temporal and spatial relationships between vascular, glomerular, and tubular changes in hypertensive renal disease remain unclear. Afferent arteriolar wall hypertrophy and glomerular capillary collapse have been observed and correlated with reduced glomerular and tubular flow in SHR, suggesting a causal relationship between afferent arteriolopathy and tubular injury.102 Thickening of the interlobular artery has been shown with infiltration of lymphocytes, VSMC proliferation, and imbalance of collagen metabolism featuring increased synthesis and inhibition of breakdown leading to fibrosis.95,103 Changes in vascular function and morphology precede renal damage in SHR, further indicating their importance in the pathogenesis of hypertensive renal disease.99,104,105 Whether vascular dysfunction is present in the renal vasculature prior to observable morphologic changes is poorly understood. Both angiotensin receptor blockers and calcium channel blockers have been shown to reduce glomerular sclerosis and arteriolar wall thickening in experimental animals; however, if this is due to mechanisms beyond their blood pressure–lowering effects remains unclear.106–108 It is well established that chronic activation of the innate immune system contributes to both hypertension and kidney injury. Work in our laboratory has shown increased circulation of mitochondrial DNA in SHR6 with associated systemic inflammation and vascular dysfunction via formyl peptide receptor activation. These findings were reproduced in isolated intrarenal arteries of normotensive rats exposed to mitochondrial fragments and were not attenuated with thiazide diuretic treatment despite lowering blood pressure (unpublished data). The effects of inflammation and chronic immune system activation on the development of renal dysfunction in hypertension-associated dysfunction remain largely unclear and represent an exciting avenue for future study. Cerebral circulation Hypertension has devastating effects on the brain. It is the leading cause of stroke and a major cause of dementia and cognitive impairment. The cerebral vasculature has several important structural and functional differences from the peripheral circulation, which serve to maintain continuous perfusion. Surface pial arteries form an effective collateral network, and occlusion of a single vessel does not significantly reduce cerebral blood flow. However, downstream-penetrating and parenchymal arterioles are largely unbranched, and a single-vessel occlusion can significantly reduce blood flow and result in ischemia.109Table 2 summarizes several important structural and functional changes in cerebral arteries during hypertension. Table 2. Summary of hypertension-associated dysfunction in cerebral arteries Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Abbreviation: ACEI, angiotensin converting enzyme inhibitors; SHR, spontaneously hypertensive rats. View Large Table 2. Summary of hypertension-associated dysfunction in cerebral arteries Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Abbreviation: ACEI, angiotensin converting enzyme inhibitors; SHR, spontaneously hypertensive rats. View Large The effects of hypertension on the cerebral circulation are numerous and complex and have been reviewed extensively elsewhere.110,111 The deleterious effects of hypertension in the brain include vessel rarefaction, artery remodeling, and hypertrophy, changes in vascular myogenic reactivity, and endothelial dysfunction with compromise of the blood–brain barrier. Numerous cell types play a unique role in the cerebral circulation, and their role in hypertension is summarized in Table 3. Table 3. Summary of cell types involved in hypertension-associated dysfunction of the cerebral vasculature Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Abbreviations: BBB, blood–brain barrier; ICAM, intercellular adhesion molecule; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell. View Large Table 3. Summary of cell types involved in hypertension-associated dysfunction of the cerebral vasculature Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Abbreviations: BBB, blood–brain barrier; ICAM, intercellular adhesion molecule; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell. View Large Hepatic circulation The liver receives one-third of its blood supply from the hepatic artery and the remaining two-thirds from the portal vein. Its immense vascularization is highlighted by the fact that it receives 25% of cardiac output despite only comprising 2% of body weight. This is accomplished by a pressure gradient of only a few millimeters of mercury. Due to extremely distensible capacitance and venous resistance sites, the liver plays a crucial role in response to decreased or increased blood volume and has a recognized role in determining the response to vasopressors, antihypertensives, and afterload-reducing agents.112 Essential hypertension is strongly linked to the development of nonalcoholic fatty liver disease.113 Both, nonalcoholic fatty liver disease and hypertension are well-established components of metabolic syndrome, and their relationship appears to be related to increased insulin resistance and total body weight.114 Hypertension is also associated with nonalcoholic fatty liver disease independent of body mass, highlighting the importance of evaluating hypertensive patients for the development of liver disease and vice versa.115 Interestingly, patients with hypertension are likely to become normotensive as cirrhosis develops, and hypertension is rarely manifested in patients with established cirrhosis.116 This is likely due to an overall vasodilatory state in cirrhosis mediated through complex, interconnected mechanisms including adrenomedullin, calcitonin gene-related peptide, nitric oxide, and other vasodilators present in the splanchnic vascular bed.116 The above observations highlight the complex role of the hepatic circulation in altering systemic hemodynamics in both the healthy and pathologic states. CONCLUSION Vascular dysfunction is undoubtedly associated with the genesis and/or maintenance of hypertension. Although endothelial cells and VSMCs dysfunction are the most commonly associated culprit for the vascular changes seen in hypertension, evidence shows that other cell types within the vasculature are also involved in this phenomenon (summarized in Figure 3a,b). Unfortunately, specific markers and/or pharmacological agents that are able to differentiate cells for specific interventions are limited or simply do not exist. It is of critical importance to understand the basic physiologic role of each cell type within the vasculature and identify their contributions to the development of vascular dysfunction in hopes that new targeted therapies can be produced. Figure 3. View largeDownload slide Representative images comparing vascular changes between resistance arteries from normotensive (a) and hypertensive (b) model. When comparing hypertensive resistance arteries with normotensive ones, it is important to note that endothelial cells are damaged and express adhesion molecules, VSMC hypertrophy and hyperplasia, increase in number of infiltrating cells between the medial layer and adventitial layer, increased collagen deposition, and increased number of resident fibrocytes. Figure 3. View largeDownload slide Representative images comparing vascular changes between resistance arteries from normotensive (a) and hypertensive (b) model. When comparing hypertensive resistance arteries with normotensive ones, it is important to note that endothelial cells are damaged and express adhesion molecules, VSMC hypertrophy and hyperplasia, increase in number of infiltrating cells between the medial layer and adventitial layer, increased collagen deposition, and increased number of resident fibrocytes. ACKNOWLEDGMENTS We would like to acknowledge Drs O’Connor and Crislip from the Department of Physiology at Augusta University, who kindly provided Figure 2 for this manuscript. We also would like to thank Lynsey Ekema, MSMI, for her artistic contribution to our Figure 3a,b. The work is funded by NIH through grant numbers P01 HL134604 and 1K99GM118885-01. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/ PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults . A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, 2017. 2. Fry DL. Acute vascular endothelial changes associated with increased blood velocity gradients. Circ Res  1968; 22: 165– 197. Google Scholar CrossRef Search ADS PubMed  3. Fry DL. Certain histological and chemical responses of the vascular interface to acutely induced mechanical stress in the aorta of the dog. Circ Res  1969; 24: 93– 108. Google Scholar CrossRef Search ADS PubMed  4. Vaziri ND, Ni Z, Oveisi F. Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension  1998; 31: 1248– 1254. Google Scholar CrossRef Search ADS PubMed  5. Wenceslau CF, McCarthy CG, Szasz T, Goulopoulou S, Webb RC. Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome. Am J Physiol Heart Circ Physiol  2015; 308: H768– H777. Google Scholar CrossRef Search ADS PubMed  6. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res  2015; 107: 119– 130. Google Scholar CrossRef Search ADS PubMed  7. Schmid-Schoenbein GW, Fung YC, Zweifach BW. Vascular endothelium-leukocyte interaction; sticking shear force in venules. Circ Res  1975; 36: 173– 184. Google Scholar CrossRef Search ADS PubMed  8. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension  2014; 63: 572– 579. Google Scholar CrossRef Search ADS PubMed  9. Kirsch T, Beese M, Wyss K, Klinge U, Haller H, Haubitz M, Fiebeler A. Aldosterone modulates endothelial permeability and endothelial nitric oxide synthase activity by rearrangement of the actin cytoskeleton. Hypertension  2013; 61: 501– 508. Google Scholar CrossRef Search ADS PubMed  10. Hall A. Rho GTPases and the actin cytoskeleton. Science  1998; 279: 509– 514. Google Scholar CrossRef Search ADS PubMed  11. Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol  2013; 62: 341– 354. Google Scholar CrossRef Search ADS PubMed  12. Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci  2016; 73: 57– 77. Google Scholar CrossRef Search ADS PubMed  13. Mehta D, Ravindran K, Kuebler WM. Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol  2014; 307: L924– L935. Google Scholar CrossRef Search ADS PubMed  14. Pitas RE, Boyles J, Mahley RW, Bissell DM. Uptake of chemically modified low density lipoproteins in vivo is mediated by specific endothelial cells. J Cell Biol  1985; 100: 103– 117. Google Scholar CrossRef Search ADS PubMed  15. Piper PJ, Vane JR, Wyllie JH. Inactivation of prostaglandins by the lungs. Nature  1970; 225: 600– 604. Google Scholar CrossRef Search ADS PubMed  16. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun  1995; 209: 483– 489. Google Scholar CrossRef Search ADS PubMed  17. Jeffery TK, Bryan-Lluka LJ, Wanstall JC. Specific uptake of 5-hydroxytryptamine is reduced in lungs from hypoxic pulmonary hypertensive rats. Eur J Pharmacol  2000; 396: 137– 140. Google Scholar CrossRef Search ADS PubMed  18. Vanhoutte PM. Serotonin and the blood-vessel wall. J Hypertens Suppl  1986; 4: S112– S115. Google Scholar PubMed  19. Pucovský V. Interstitial cells of blood vessels. ScientificWorldJournal  2010; 10: 1152– 1168. Google Scholar CrossRef Search ADS PubMed  20. Pucovsky V, Moss RF, Bolton TB. Non-contractile cells with thin processes resembling interstitial cells of Cajal found in the wall of guinea-pig mesenteric arteries. J Physiol  2003; 552: 119– 133. Google Scholar CrossRef Search ADS PubMed  21. Harhun MI, Szewczyk K, Laux H, Prestwich SA, Gordienko DV, Moss RF, Bolton TB. Interstitial cells from rat middle cerebral artery belong to smooth muscle cell type. J Cell Mol Med  2009; 13: 4532– 4539. Google Scholar CrossRef Search ADS PubMed  22. Povstyan OV, Gordienko DV, Harhun MI, Bolton TB. Identification of interstitial cells of Cajal in the rabbit portal vein. Cell Calcium  2003; 33: 223– 239. Google Scholar CrossRef Search ADS PubMed  23. Harhun MI, Pucovský V, Povstyan OV, Gordienko DV, Bolton TB. Interstitial cells in the vasculature. J Cell Mol Med  2005; 9: 232– 243. Google Scholar CrossRef Search ADS PubMed  24. Bobryshev YV. Subset of cells immunopositive for neurokinin-1 receptor identified as arterial interstitial cells of Cajal in human large arteries. Cell Tissue Res  2005; 321: 45– 55. Google Scholar CrossRef Search ADS PubMed  25. Ghose D, L J, Manjunatha S, MS R, Rao JP. Inherent rhythmicity and interstitial cells of Cajal in a frog vein. J Biosci  2008; 33: 755– 759. Google Scholar CrossRef Search ADS PubMed  26. Morel E, Meyronet D, Thivolet-Bejuy F, Chevalier P. Identification and distribution of interstitial Cajal cells in human pulmonary veins. Heart Rhythm  2008; 5: 1063– 1067. Google Scholar CrossRef Search ADS PubMed  27. Bolton TB, Gordienko DV, Povstyan OV, Harhun MI, Pucovsky V. Smooth muscle cells and interstitial cells of blood vessels. Cell Calcium  2004; 35: 643– 657. Google Scholar CrossRef Search ADS PubMed  28. Lou Z, Li JS. Interstitial cells of Cajal in abdominal sepsis and hypertension-induced ileus in rats. Eur Surg Res  2009; 43: 47– 52. Google Scholar CrossRef Search ADS PubMed  29. Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. Circ Res  1994; 75: 41– 54. Google Scholar CrossRef Search ADS PubMed  30. Szasz T, Tostes RCA. Vascular smooth muscle function in hypertension. Colloquium Series on Integrated Systems Physiology: From Molecule to Function . 2016; 8: i– 96. 31. Mulvany MJ. Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res  1999; 41: 9– 13. Google Scholar CrossRef Search ADS PubMed  32. Mulvany MJ. Small artery remodelling in hypertension. Basic Clin Pharmacol Toxicol  2012; 110: 49– 55. Google Scholar CrossRef Search ADS PubMed  33. Folkow B, Grimby G, Thulesius O. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Acta Physiol Scand  1958; 44: 255– 272. Google Scholar CrossRef Search ADS PubMed  34. Castorena-Gonzalez JA, Staiculescu MC, Foote C, Martinez-Lemus LA. Mechanisms of the inward remodeling process in resistance vessels: is the actin cytoskeleton involved? Microcirculation  2014; 21: 219– 229. Google Scholar CrossRef Search ADS PubMed  35. Hadrava V, Kruppa U, Russo RC, Lacourcière Y, Tremblay J, Hamet P. Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. Am Heart J  1991; 122: 1198– 1203. Google Scholar CrossRef Search ADS PubMed  36. Cipolla MJ, Gokina NI, Osol G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J  2002; 16: 72– 76. Google Scholar CrossRef Search ADS PubMed  37. Staiculescu MC, Galiñanes EL, Zhao G, Ulloa U, Jin M, Beig MI, Meininger GA, Martinez-Lemus LA. Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling. Cardiovasc Res  2013; 98: 428– 436. Google Scholar CrossRef Search ADS PubMed  38. Yamin R, Morgan KG. Deciphering actin cytoskeletal function in the contractile vascular smooth muscle cell. J Physiol  2012; 590: 4145– 4154. Google Scholar CrossRef Search ADS PubMed  39. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med  1994; 1: 71– 81. Google Scholar PubMed  40. Li J, Tan H, Wang X, Li Y, Samuelson L, Li X, Cui C, Gerber DA. Circulating fibrocytes stabilize blood vessels during angiogenesis in a paracrine manner. Am J Pathol  2014; 184: 556– 571. Google Scholar CrossRef Search ADS PubMed  41. Reilkoff RA, R B, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol  2011; 11: 427– 435. Google Scholar CrossRef Search ADS PubMed  42. Rios FJ, Harvey A, Lopes RA, Montezano AC, Touyz RM. Progenitor cells, bone marrow-derived fibrocytes and endothelial-to-mesenchymal transition: new players in vascular fibrosis. Hypertension  2016; 67: 272– 274. Google Scholar PubMed  43. Safar ME. Arterial stiffness as a risk factor for clinical hypertension. Nat Rev Cardiol  2017. 44. Wu J, Montaniel KR, Saleh MA, Xiao L, Chen W, Owens GK, Humphrey JD, Majesky MW, Paik DT, Hatzopoulos AK, Madhur MS, Harrison DG. Origin of matrix-producing cells that contribute to aortic fibrosis in hypertension. Hypertension  2016; 67: 461– 468. Google Scholar PubMed  45. Andersson-Sjöland A, Erjefält JS, Bjermer L, Eriksson L, Westergren-Thorsson G. Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis. Respir Res  2009; 10: 103. Google Scholar CrossRef Search ADS PubMed  46. Medbury HJ, Tarran SL, Guiffre AK, Williams MM, Lam TH, Vicaretti M, Fletcher JP. Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes. Int Angiol  2008; 27: 114– 123. Google Scholar PubMed  47. Ogbi S, Webb RC. Fibrocyte markers are increased in pudendal artery of spontaneously hypertensive rats (SHR). FASEB J  2016; 30: lb617. 48. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol  2013; 75: 23– 47. Google Scholar CrossRef Search ADS PubMed  49. Sorrell JM, Caplan AI. Fibroblasts-a diverse population at the center of it all. Int Rev Cell Mol Biol  2009; 276: 161– 214. Google Scholar CrossRef Search ADS PubMed  50. Yuan W, Liu W, Li J, Li X, Sun X, Xu F, Man X, Fu Q. Effects of BMSCs interactions with adventitial fibroblasts in transdifferentiation and ultrastructure processes. Int J Clin Exp Pathol  2014; 7: 3957– 3965. Google Scholar PubMed  51. McGrath JC, Deighan C, Briones AM, Shafaroudi MM, McBride M, Adler J, Arribas SM, Vila E, Daly CJ. New aspects of vascular remodelling: the involvement of all vascular cell types. Exp Physiol  2005; 90: 469– 475. Google Scholar CrossRef Search ADS PubMed  52. Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell  2011; 21: 193– 215. Google Scholar CrossRef Search ADS PubMed  53. van Dijk CG, Nieuweboer FE, Pei JY, Xu YJ, Burgisser P, van Mulligen E, el Azzouzi H, Duncker DJ, Verhaar MC, Cheng C. The complex mural cell: pericyte function in health and disease. Int J Cardiol  2015; 190: 75– 89. Google Scholar CrossRef Search ADS PubMed  54. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab  2016; 36: 451– 455. 55. Hartmann DA, Underly RG, Grant RI, Watson AN, Lindner V, Shih AY. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics  2015; 2: 041402. Google Scholar CrossRef Search ADS PubMed  56. Fernández-Klett F, Priller J. Diverse functions of pericytes in cerebral blood flow regulation and ischemia. J Cereb Blood Flow Metab  2015; 35: 883– 887. Google Scholar CrossRef Search ADS PubMed  57. Dore-Duffy P, Cleary K. Morphology and properties of pericytes. Methods Mol Biol  2011; 686: 49– 68. Google Scholar CrossRef Search ADS PubMed  58. Zimmermann KW. Der Feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch  1923; 68: 29– 109. Google Scholar CrossRef Search ADS   59. Krueger M, Bechmann I. CNS pericytes: concepts, misconceptions, and a way out. Glia  2010; 58: 1– 10. Google Scholar CrossRef Search ADS PubMed  60. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab  2013; 33: 1732– 1742. Google Scholar CrossRef Search ADS PubMed  61. Herman IM, Jacobson S. In situ analysis of microvascular pericytes in hypertensive rat brains. Tissue Cell  1988; 20: 1– 12. Google Scholar CrossRef Search ADS PubMed  62. Yuan K, Shao NY, Hennigs JK, Discipulo M, Orcholski ME, Shamskhou E, Richter A, Hu X, Wu JC, de Jesus Perez VA. Increased pyruvate dehydrogenase kinase 4 expression in lung pericytes is associated with reduced endothelial-pericyte interactions and small vessel loss in pulmonary arterial hypertension. Am J Pathol  2016; 186: 2500– 2514. Google Scholar CrossRef Search ADS PubMed  63. Wang S, Zeng H, Xie XJ, Tao YK, He X, Roman RJ, Aschner JL, Chen JX. Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget  2016; 7: 58848– 58861. Google Scholar PubMed  64. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation  2014; 129: 1586– 1597. Google Scholar CrossRef Search ADS PubMed  65. Soltis EE, Cassis LA. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A  1991; 13: 277– 296. Google Scholar PubMed  66. Aghamohammadzadeh R, Heagerty AM. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. Ann Med  2012; 44: S74– 84. Google Scholar CrossRef Search ADS PubMed  67. Aghamohammadzadeh R, Withers S, Lynch F, Greenstein A, Malik R, Heagerty A. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Br J Pharmacol  2012; 165: 670– 682. Google Scholar CrossRef Search ADS PubMed  68. Akoumianakis I, Tarun A, Antoniades C. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. Br J Pharmacol  2017; 174: 3411– 3424. Google Scholar CrossRef Search ADS PubMed  69. Brandes RP. The fatter the better? Perivascular adipose tissue attenuates vascular contraction through different mechanisms. Br J Pharmacol  2007; 151: 303– 304. Google Scholar CrossRef Search ADS PubMed  70. Chaldakov GN, Fiore M, Ghenev PI, Beltowski J, Ranćić G, Tunçel N, Aloe L. Triactome: neuro-immune-adipose interactions. Implication in vascular biology. Front Immunol  2014; 5: 130. Google Scholar CrossRef Search ADS PubMed  71. Chaldakov GN, Fiore M, Rancic G, Gehenev P, Tuncel N, Beltowski Jet al.   Rethinking vascular wall: periadventitial adipose tissue (tunica adiposa). Obes Metab  2010; 6: 46– 9. 72. Eringa EC, Bakker W, van Hinsbergh VW. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Vascul Pharmacol  2012; 58: 204– 209. Google Scholar CrossRef Search ADS   73. Gollasch M, Dubrovska G. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Trends Pharmacol Sci  2004; 25: 647– 653. Google Scholar CrossRef Search ADS PubMed  74. Kennedy S, Salt IP. Molecular mechanisms regulating perivascular adipose tissue—potential pharmacological targets? Br J Pharmacol  2017; 174: 3385– 3387. Google Scholar CrossRef Search ADS PubMed  75. Szasz T, Webb RC. Perivascular adipose tissue: more than just structural support. Clin Sci (Lond)  2012; 122: 1– 12. Google Scholar CrossRef Search ADS PubMed  76. Ramirez JG, O’Malley EJ, Ho WSV. Pro-contractile effects of perivascular fat in health and disease. Br J Pharmacol  2017; 2017: 20. 77. Rajsheker S, Manka D, Blomkalns AL, Chatterjee TK, Stoll LL, Weintraub NL. Crosstalk between perivascular adipose tissue and blood vessels. Curr Opin Pharmacol  2010; 10: 191– 196. Google Scholar CrossRef Search ADS PubMed  78. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med  2007; 204: 2449– 2460. Google Scholar CrossRef Search ADS PubMed  79. Srikakulapu P, Upadhye A, Rosenfeld SM, Marshall MA, McSkimming C, Hickman AW, Mauldin IS, Ailawadi G, Lopes MBS, Taylor AM, McNamara CA. Perivascular adipose tissue harbors atheroprotective IgM-producing B cells. Front Physiol  2017; 8: 719. Google Scholar CrossRef Search ADS PubMed  80. Withers SB, Forman R, Meza-Perez S, Sorobetea D, Sitnik K, Hopwood T, Lawrence CB, Agace WW, Else KJ, Heagerty AM, Svensson-Frej M, Cruickshank SM. Eosinophils are key regulators of perivascular adipose tissue and vascular functionality. Sci Rep  2017; 7: 44571. Google Scholar CrossRef Search ADS PubMed  81. Krautler NJ, Kana V, Kranich J, Tian Y, Perera D, Lemm D, Schwarz P, Armulik A, Browning JL, Tallquist M, Buch T, Oliveira-Martins JB, Zhu C, Hermann M, Wagner U, Brink R, Heikenwalder M, Aguzzi A. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell  2012; 150: 194– 206. Google Scholar CrossRef Search ADS PubMed  82. Ji H, Pai AV, West CA, Wu X, Speth RC, Sandberg K. Loss of resistance to angiotensin II-induced hypertension in the Jackson laboratory recombination-activating gene null mouse on the C57BL/6J background. Hypertension  2017; 69: 1121– 1127. Google Scholar CrossRef Search ADS PubMed  83. Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res  2017; 113: 1009– 1023. Google Scholar CrossRef Search ADS PubMed  84. Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res  2012; 110: 889– 900. Google Scholar CrossRef Search ADS PubMed  85. Fernández-Alfonso MS, Gil-Ortega M, Aranguez I, Souza D, Dreifaldt M, Somoza B, Dashwood MR. Role of PVAT in coronary atherosclerosis and vein graft patency: friend or foe? Br J Pharmacol  2017; 174: 3561– 3572. Google Scholar CrossRef Search ADS PubMed  86. Mikolajczyk TP, Nosalski R, Szczepaniak P, Budzyn K, Osmenda G, Skiba D, Sagan A, Wu J, Vinh A, Marvar PJ, Guzik B, Podolec J, Drummond G, Lob HE, Harrison DG, Guzik TJ. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. FASEB J  2016; 30: 1987– 1999. Google Scholar CrossRef Search ADS PubMed  87. Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol  2017; 174: 3496– 3513. Google Scholar CrossRef Search ADS PubMed  88. CS BKF. Ectopic fat deposits and cardiovascular disease. Circulation  2011; 124: e837– e41. CrossRef Search ADS PubMed  89. Coffman TM. The inextricable role of the kidney in hypertension. J Clin Invest  2014; 124: 2341– 2347. Google Scholar CrossRef Search ADS PubMed  90. Guyton AC, Coleman TG, Cowley AVJr, Scheel KW, Manning RDJr, Norman RAJr. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med  1972; 52: 584– 594. Google Scholar CrossRef Search ADS PubMed  91. McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, Chambon P, Hill MA, Dorrance AM, Mendelsohn ME, Jaffe IZ. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med  2012; 18: 1429– 1433. Google Scholar CrossRef Search ADS PubMed  92. Michael SK, Surks HK, Wang Y, Zhu Y, Blanton R, Jamnongjit M, Aronovitz M, Baur W, Ohtani K, Wilkerson MK, Bonev AD, Nelson MT, Karas RH, Mendelsohn ME. High blood pressure arising from a defect in vascular function. Proc Natl Acad Sci USA  2008; 105: 6702– 6707. Google Scholar CrossRef Search ADS PubMed  93. Osborn JW, Fink GD, Kuroki MT. Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation. Curr Hypertens Rep  2011; 13: 221– 228. Google Scholar CrossRef Search ADS PubMed  94. Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani A, Kasiske B, Liu J, Mau LW, McBean M, Murray A, St Peter W, Guo H, Gustafson S, Li Q, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L. US Renal Data System 2010 Annual Data Report. Am J Kidney Dis  2011; 57: A8, e1– A8, 526. Google Scholar CrossRef Search ADS   95. Hultström M, Leh S, Skogstrand T, Iversen BM. Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage. Nephrol Dial Transplant  2008; 23: 896– 903. Google Scholar CrossRef Search ADS PubMed  96. Ochodnický P, Henning RH, Buikema HJ, de Zeeuw D, Provoost AP, van Dokkum RP. Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat. Am J Physiol Renal Physiol  2010; 298: F625– F633. Google Scholar CrossRef Search ADS PubMed  97. Skogstrand T, Leh S, Paliege A, Reed RK, Vikse BE, Bachmann S, Iversen BM, Hultström M. Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats. J Hypertens  2013; 31: 152– 159. Google Scholar CrossRef Search ADS PubMed  98. Ito S, Nagasawa T, Abe M, Mori T. Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk. Hypertens Res  2009; 32: 115– 121. Google Scholar CrossRef Search ADS PubMed  99. Iversen BM, Amann K, Kvam FI, Wang X, Ofstad J. Increased glomerular capillary pressure and size mediate glomerulosclerosis in SHR juxtamedullary cortex. Am J Physiol  1998; 274: F365– F373. Google Scholar CrossRef Search ADS PubMed  100. Johnson RJ, Gordon KL, Giachelli C, Kurth T, Skelton MM, Cowley AWJr. Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS rat. J Hypertens  2000; 18: 1497– 1505. Google Scholar CrossRef Search ADS PubMed  101. Mori T, Cowley AWJr. Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats. Hypertension  2004; 43: 752– 759. Google Scholar CrossRef Search ADS PubMed  102. Leh S, Hultström M, Rosenberger C, Iversen BM. Afferent arteriolopathy and glomerular collapse but not segmental sclerosis induce tubular atrophy in old spontaneously hypertensive rats. Virchows Arch  2011; 459: 99– 108. Google Scholar CrossRef Search ADS PubMed  103. Ofstad J, Iversen BM. Glomerular and tubular damage in normotensive and hypertensive rats. Am J Physiol Renal Physiol  2005; 288: F665– F672. Google Scholar CrossRef Search ADS PubMed  104. Kimura K, Nanba S, Tojo A, Hirata Y, Matsuoka H, Sugimoto T. Variations in arterioles in spontaneously hypertensive rats. Morphometric analysis of afferent and efferent arterioles. Virchows Arch A Pathol Anat Histopathol  1989; 415: 565– 569. Google Scholar CrossRef Search ADS PubMed  105. Skov K, Mulvany MJ. Structure of renal afferent arterioles in the pathogenesis of hypertension. Acta Physiol Scand  2004; 181: 397– 405. Google Scholar CrossRef Search ADS PubMed  106. Aoki Y, Kai H, Kajimoto H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kage M, Kato S, Fukumoto Y, Imaizumi T. Large blood pressure variability aggravates arteriolosclerosis and cortical sclerotic changes in the kidney in hypertensive rats. Circ J  2014; 78: 2284– 2291. Google Scholar CrossRef Search ADS PubMed  107. Aritomi S, Koganei H, Wagatsuma H, Mitsui A, Ogawa T, Nitta K, Konda T. The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet. Heart Vessels  2010; 25: 549– 555. Google Scholar CrossRef Search ADS PubMed  108. Eliahou H, Avinoach I, Shahmurov M, Ben-David A, Shahar C, Matas Z, Zimlichman R. Renoprotective effect of angiotensin II receptor antagonists in experimental chronic renal failure. Am J Nephrol  2001; 21: 78– 83. Google Scholar CrossRef Search ADS PubMed  109. Nishimura N, Schaffer CB, Friedman B, Lyden PD, Kleinfeld D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci USA  2007; 104: 365– 370. Google Scholar CrossRef Search ADS PubMed  110. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol  2013; 304: H1598– H1614. Google Scholar CrossRef Search ADS PubMed  111. Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab  2008; 7: 476– 484. Google Scholar CrossRef Search ADS PubMed  112. Lautt WW. Hepatic circulation: physiology and pathophysiology. In CTI - Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease , Morgan & Claypool Life Sciences, 2009. Google Scholar CrossRef Search ADS   113. Brookes MJ, Cooper BT. Hypertension and fatty liver: guilty by association? J Hum Hypertens  2007; 21: 264– 270. Google Scholar CrossRef Search ADS PubMed  114. Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, Bolondi L. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut  2004; 53: 1020– 1023. Google Scholar CrossRef Search ADS PubMed  115. Michopoulos S, Chouzouri VI, Manios ED, Grapsa E, Antoniou Z, Papadimitriou CA, Zakopoulos N, Dimopoulos AM. Untreated newly diagnosed essential hypertension is associated with nonalcoholic fatty liver disease in a population of a hypertensive center. Clin Exp Gastroenterol  2016; 9: 1– 9. Google Scholar CrossRef Search ADS PubMed  116. Henriksen JH, Moller S. Liver cirrhosis and arterial hypertension. World J Gastroenterol  2006; 12: 678– 685. Google Scholar CrossRef Search ADS PubMed  117. Klee NS, McCarthy CG, Martinez-Quinones P, Webb RC. Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy. Ther Adv Cardiovasc Dis  2017; 11: 297– 317. Google Scholar CrossRef Search ADS PubMed  118. Kapustin AN, Chatrou ML, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RT, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res  2015; 116: 1312– 1323. Google Scholar CrossRef Search ADS PubMed  119. Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, Kaneko S. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA  2006; 103: 14098– 14103. Google Scholar CrossRef Search ADS PubMed  120. Coyle P, Heistad DD. Blood flow through cerebral collateral vessels in hypertensive and normotensive rats. Hypertension  1986; 8: Ii67– Ii 71. Google Scholar CrossRef Search ADS PubMed  121. Omura-Matsuoka E, Yagita Y, Sasaki T, Terasaki Y, Oyama N, Sugiyama Y, Todo K, Sakoda S, Kitagawa K. Hypertension impairs leptomeningeal collateral growth after common carotid artery occlusion: restoration by antihypertensive treatment. J Neurosci Res  2011; 89: 108– 116. Google Scholar CrossRef Search ADS PubMed  122. Cipolla MJ, Li R, Vitullo L. Perivascular innervation of penetrating brain parenchymal arterioles. J Cardiovasc Pharmacol  2004; 44: 1– 8. Google Scholar CrossRef Search ADS PubMed  123. Mulvany MJ. Small artery remodeling and significance in the development of hypertension. News Physiol Sci  2002; 17: 105– 109. Google Scholar PubMed  124. Dupuis F, Atkinson J, Limiñana P, Chillon JM. Captopril improves cerebrovascular structure and function in old hypertensive rats. Br J Pharmacol  2005; 144: 349– 356. Google Scholar CrossRef Search ADS PubMed  125. Sokolova IA, Manukhina EB, Blinkov SM, Koshelev VB, Pinelis VG, Rodionov IM. Rarefication of the arterioles and capillary network in the brain of rats with different forms of hypertension. Microvasc Res  1985; 30: 1– 9. Google Scholar CrossRef Search ADS PubMed  126. Miller AA, Budzyn K, Sobey CG. Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention. Clin Sci (Lond)  2010; 119: 1– 17. Google Scholar CrossRef Search ADS PubMed  127. Giachini FR, Carneiro FS, Lima VV, Carneiro ZN, Dorrance A, Webb RC, Tostes RC. Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats. Transl Res  2009; 154: 183– 193. Google Scholar CrossRef Search ADS PubMed  128. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol  2013; 304: H1598– H1614. Google Scholar CrossRef Search ADS PubMed  129. Nishimura N, Schaffer CB, Friedman B, Lyden PD, Kleinfeld D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci USA  2007; 104: 365– 370. Google Scholar CrossRef Search ADS PubMed  130. Tagami M, Nara Y, Kubota A, Fujino H, Yamori Y. Ultrastructural changes in cerebral pericytes and astrocytes of stroke-prone spontaneously hypertensive rats. Stroke  1990; 21: 1064– 1071. Google Scholar CrossRef Search ADS PubMed  131. Dore-Duffy P, LaManna JC. Physiologic angiodynamics in the brain. Antioxid Redox Signal  2007; 9: 1363– 1371. Google Scholar CrossRef Search ADS PubMed  132. Faraco G, Park L, Anrather J, Iadecola C. Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med (Berl)  2017; 95: 1143– 1152. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

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Abstract

Abstract Morphological and physiological changes in the vasculature have been described in the evolution and maintenance of hypertension. Hypertension-induced vascular dysfunction may present itself as a contributing, or consequential factor, to vascular remodeling caused by chronically elevated systemic arterial blood pressure. Changes in all vessel layers, from the endothelium to the perivascular adipose tissue (PVAT), have been described. This mini-review focuses on the current knowledge of the structure and function of the vessel layers, specifically muscular arteries: intima, media, adventitia, PVAT, and the cell types harbored within each vessel layer. The contributions of each cell type to vessel homeostasis and pathophysiological development of hypertension will be highlighted. blood pressure; cell types, hypertension, vascular, vessel wall According to the 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults by the American Heart Association and American College of Cardiology, 130/80 mm Hg rather than 140/90 mm Hg is considered elevated arterial blood pressure, and approximately, half of the United States adult population meet this criteria.1 As the United States population ages, the number of patients diagnosed with hypertension will continue to increase. The 2017 guideline reflects the recognition that arterial blood pressure measurements thought to be prehypertensive, correlate with pathophysiological changes in the cardiovascular system, and increase a patient’s risk for hypertension-associated comorbidities, including stroke and death. This new guideline highlights the importance of early identification and increased patient monitoring to prevent hypertension-related side effects. Hypertension is associated with vascular dysfunction, with changes are seen at the histological and cellular level in vessels from hypertensive animals and human patients. This mini-review reflects studies from both animal and human subjects, the majority which has been performed in animal models of hypertension. Regardless of the model subject, it is highly debated whether pathophysiological changes are one of the causes of elevated blood pressure or the effect of chronic hypertension. The current literature focuses mostly on the changes in morphology and function of endothelial and vascular smooth muscle cells (VSMCs). However, because vascular dysfunction in hypertension implicates other vascular cells, such as fibrocytes, pericytes, and even cells of the perivascular adipose tissue (PVAT), in this mini-review, we have focused our discussion on these nonendothelium vascular cell types. TUNICA INTIMA Endothelial cells The endothelium is the major interface between the vascular wall and blood and therefore is an important organ in the regulation of vascular tone and hemostasis. Despite only being a thin monolayer, the endothelium is a dynamic organ sensitive to physical forces2 exerted by the flowing blood (shear stress) and chemical signals3 that affect vascular tone, cell adhesion, platelet function, VSMC phenotype, and vessel wall inflammation. Broadly, the endothelium has 3 major functions—secretion, physical barrier properties, and metabolism—each of which changes in hypertension. The most well-known function of the endothelium is its ability to secrete vasoactive molecules (see Table 1 for a summary of vasoactive molecules involved in hypertension and released by the vessel wall cells). In healthy conditions, the endothelium regulates the abundance of diffusible vasodilatory/anticoagulatory factors that hyperpolarize the underlying vascular smooth muscle to maintain appropriate blood flow. In hypertension, there is a shift in the balance of these factors. Generally, the endothelium from both hypertensive animals and patients increases its secretion of procontractile factors and decreases its secretion of prorelaxant factors. However, there are instances where vasodilatory factors are elevated in hypertension,4 likely as a compensatory mechanism during the development phase of high blood pressure. It has also been acknowledged that endothelium-derived hyperpolarization could occur through intercellular coupling and therefore be considered a solely electrical event. There is ongoing discovery of novel vasoactive molecules that are secreted from the endothelium and directly impact vascular tone or indirectly modulate the abundance of traditional vasoactive molecules (e.g., nitric oxide bioavailability, prostaglandin synthesis). Damage-associated molecular patterns, cell components released or secreted during cell death, have emerged as novel mediators5 and modulators6 of endothelial function, acting in an autocrine, paracrine, and endocrine fashion. Table 1. Vasoactive molecules released by cells of the vessel wall during hypertension Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Abbreviations: DAMP, damage-associated molecular pattern; EDHF, endothelium-derived hyperpolarizing factor; IL, interleukin; NO, nitric oxide; PVAT, perivascular adipose tissue; TGF, transforming growth factor; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell; ?, unknown effect. View Large Table 1. Vasoactive molecules released by cells of the vessel wall during hypertension Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Cell Type  Location  Vasoactive molecule and relative abundance in hypertension (compared with normotensive controls)  Physiologic effect on vascular function in hypertension  Endothelial cell  Intima  ↓ NO  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↓ PGI2  ↑ Vasodilation        ↓ Cell aggregation and inflammation        ↓ Cell migration, thrombosis      ↓ EDHF  ↑ Vasodilation        ↓ Cell aggregation and inflammation      ↑ ET-1  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ AT-II  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ Prostaglandins  ↑ Vasoconstriction        ↑ Cell aggregation and inflammation      ↑ DAMPs117  ↑ Cell aggregation and inflammation  VSMC  Media  ↑ DAMPs6  ↑ Proinflammatory response        ↑ Vessel wall fibrosis      ↑ Matrix vesicles118  Promote vascular calcification  Fibrocyte  Media  ↑ Chemokines119  ↑ Connective tissue matrix deposition      ↑ Cytokines (TNF-α, IL-6, 8, 10)  ↑ Proinflammatory response      ↑ Growth factors (TGF-â)41  ? Endothelial and VSMC proliferation        ↑ Connective tissue matrix deposition      ↑ MMP-941  ↑ Connective tissue matrix deposition  Fibroblast  Adventitia  ↑ Chemokines  ↑ Collagen deposition      ↑ Cytokines  ↑ Proinflammatory response      ↑ Growth factors  ↑ Collagen deposition  Adipocytes  PVAT  ↑ and/or ↓ Adipokines (leptin, adiponectin, resistin, adrenomedullin, etc.)  Can be considered both pro- (leptin, resistin) and anti- inflammatory (adiponectin, adrenomedullin)      ↑ Cytokines (TNF-α, IL-1, 6,8)  ↑ Proinflammatory response      ↑ Reactive oxygen species  ↓ NO bioavailability  Pericytes  Adventitia  ↑ Growth factors  Angiogenesis/neovascularization        ↑ Vasodilation        ↓ Cell aggregation and inflammation  Abbreviations: DAMP, damage-associated molecular pattern; EDHF, endothelium-derived hyperpolarizing factor; IL, interleukin; NO, nitric oxide; PVAT, perivascular adipose tissue; TGF, transforming growth factor; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell; ?, unknown effect. View Large Endothelial cells are linked to one another via junctional structures forming a barrier. In hypertension, this barrier function is impaired, and the permeability of the endothelium increases. Endothelium dysfunction diminishes the protection of end organs and allows for increased passage of solutes and immune cells from the bloodstream, causing increased edema and inflammation.7 Prohypertensive factors contribute to endothelial barrier dysfunction. For example, angiotensin-II (Ang-II) disrupts the blood–brain barrier in spontaneously hypertensive rats (SHR),8 and aldosterone can diminish endothelial nitric oxide synthase activity via rearrangement of the actin cytoskeleton.9 Furthermore, as RhoA is generally considered the master regulator of actin cytoskeleton formation,10 an improvement in endothelial barrier function could be another mechanism of how RhoA/ROCK inhibition (e.g., fasudil) acts as an antihypertensive therapy.11 Similar to vasoactive molecules, novel mediators of endothelial permeability and actin cytoskeleton dynamics are emerging.12,13 Whether these novel factors contribute to the pathogenesis of hypertension is currently an unexplored area of research. Finally, the endothelium can also function as a metabolic unit, with a host of proteolytic enzymes and transporters that take up and process circulating molecules. The endothelium can clear prohypertensive molecules such as low-density lipoprotein,14 prostaglandins,15 and endothelin-1.16 In hypertension, however, the metabolism of endothelial cells becomes dysfunctional promoting a procontractile, proinflammatory, and pro-oxidative milieu. For example, uptake of the above mentioned prohypertensive molecules, as well as their destruction into inactive metabolites (e.g., serotonin) is impaired.17,18 In summary, it is well established that the secretory, barrier, and metabolic function of the endothelium becomes ineffective at maintaining the necessary degree of vascular homeostasis, and this promotes the development and maintenance of hypertension. However, still being revealed are multiple and intertwining mechanisms underlying the endothelium dysfunction, beyond high blood pressure itself, as well as the multiple ways that the endothelium can exert autocrine, paracrine, and endocrine influences on itself and the other organs involved in the etiology of hypertension. Interstitial cells of Cajal The interstitial cells of Cajal are a subpopulation of cells found in tissues containing smooth muscle. They are irregular in shape, contain thin processes, and are noncontractile.19 The presence and function of interstitial cells within the vasculature have not been greatly characterized. The location of these cells varies depending on tissue type, ranging from the subendothelial layer to the media-adventitia border of veins (portal, pulmonary, postcaval) and arteries (mesenteric, cerebral, aortic, carotid).20–26 Interstitial cells of Cajal exhibit pacemaker activity within veins, whereas their function in arteries is less clear. Some evidence suggests these cells have roles in angiogenesis, intercellular communication, and vessel maintenance.27 Knowledge on the role of vascular interstitial cells of Cajal in hypertension is greatly lacking, which may be a consequence of the inconsistency in nomenclature and/or lack of biomarkers. However, one study demonstrated that hypertension induced partial loss and rupture of these cells, and this was associated with a disturbance in intestinal smooth muscle cell contraction.28 Therefore, it is reasonable to hypothesize that functional and structural changes within the vascular interstitial cells of Cajal may play a role in the development and/or maintenance of hypertension. TUNICA MEDIA Vascular smooth muscle cells Total peripheral resistance is defined by Poiseuille’s law, in which 3 factors are the primary determinants of the resistance to blood flow within a vessel: lumen diameter, vessel length, and viscosity of the blood. The most significant is the lumen diameter, given that vessel resistance is inversely proportional to the radius to the fourth power (r4). Therefore, a 50% reduction in radius should increase resistance 16-fold. Adjustments in total peripheral resistance are directly determined by alterations in the morphology and/or function of VSMCs. Under physiological conditions, VSMCs are embedded in a network of elastin-rich extracellular matrix and the basement membrane, which surrounds each VSMCs and separates the VSMCs-containing medial cell layer from the endothelium.29 The basement membrane acts as a barrier to VSMCs migration, proliferation, and hypertrophy. VSMCs structural changes in hypertension are collectively termed vascular remodeling. It is observed when there is a change in diameter of a fully relaxed vessel that is not explained by a change in transmural pressure or compliance and thus is structural in nature.30 Vascular remodeling is classified as hypertrophic, eutrophic, or hypotrophic. Furthermore, remodeling can be inward (reduced luminal diameter) (Figure 1) or outward (increased luminal diameter).31,32 In hypertension, increased peripheral resistance associated to structural changes (remodeling) of the vasculature was proposed in the 1950s by Folkow.33 The most common type in hypertension is inward remodeling, causing a reduction of the luminal diameter under passive conditions. Outward remodeling is generally seen during antihypertensive treatment and in conditions of increased flow.31 In inward eutrophic remodeling, wall cross-sectional area will be preserved by repositioning of the VSMCs, which normalizes the circumferential stress of the resistance vessel exposed to increased blood pressure. It is suggested that the inward eutrophic remodeling precedes and prevents hypertrophy if the rearrangement effectively normalizes the circumferential stress. However, if the rearrangement does not occur, VSMCs are stimulated and the cross-sectional area is injured.34 These structural changes increase the wall-to-lumen ratio which causes an increase in the peripheral resistance. Figure 1. View largeDownload slide Arterial remodeling in hypertension. Typical representative images of mesenteric resistance arteries from Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) showing the inward remodeling in SHR arteries. Confocal images (×40 magnification) of increased colocalization immunofluorescence for Toll-like receptor 9 (red) and MyD88 (green). Figure 1. View largeDownload slide Arterial remodeling in hypertension. Typical representative images of mesenteric resistance arteries from Wistar–Kyoto (WKY) and spontaneously hypertensive rats (SHR) showing the inward remodeling in SHR arteries. Confocal images (×40 magnification) of increased colocalization immunofluorescence for Toll-like receptor 9 (red) and MyD88 (green). Consistent findings demonstrate that during hypertension, VSMCs hyperplasia and hypertrophy represents 2 of the crucial anomalies responsible for the vascular inward remodeling and subsequent development of increased total peripheral resistance.30 Interestingly, the exaggerated response of VSMCs to growth factors in SHR persists in cell culture, indicating an intrinsic defect in hypertension-associated VSMCs hyperplasia and hypertrophy.35 For instance, many of the same factors that induce experimental hypertension also induce hypertrophy and hyperplasia in VSMCs, such as Ang-II, norepinephrine, and mineralocorticoids.30 Recent evidence has revealed that actin polymerization in VSMCs contributes to vascular remodeling. Accordingly, it has been observed that pressure-induced actin polymerization in VSMCs is one mechanism underlying myogenic behavior.36 Additionally, prolonged vasoconstriction of resistance arteries also involves VSMCs actin polymerization.37 For both the mechanotransduction pathway and agonist-induced changes in actin polymerization, RhoA-CdC42 pathway has been shown to be a primary contributor.38 Functionally, Ca2+ plays a central role of in the physiology and pathophysiology of VSMCs contractility. An increase in intracellular Ca2+ concentration is essential for activation of myosin light-chain kinase (MLCK), phosphorylation of MLC, myofilament cross-bridge cycling, and contraction. For instance, Ca2+ handling changes were found in human and experimental models of hypertension, including upregulation of receptor-operated and/or store-operated Ca2+ channels expression, upregulation or downregulation of L-type Ca2+ channels, increase in Ca2+ sensitization via RhoA activation, and increased mitochondria and sarcoplasmic reticulum Ca2+ stores.30 Therefore, disturbances in the handling of Ca2+ may be the most important factor unifying different mechanisms of VSMC dysfunctions in hypertension. Fibrocytes First described by Dr Bucala’s group in 1994 as a new leukocyte subpopulation exhibiting fibroblast-related properties, fibrocytes are considered one of the first cell lines physiologically responsible for wound repair and tissue regeneration.39,40 Fibrocytes are bone marrow-derived mesenchymal progenitor cells that express stem cell (CD34), pan-hematopoietic (CD45), and monocyte markers (CD14 and 11) on their surface.40 Fibrocytes synthesize and release cytokines, metalloproteinases, and components of the connective tissue matrix (type I and III collagen, vimentin, and fibronectin), all of which contribute to tissue repair.41 The ability of fibrocytes to differentiate into fibroblasts or myofibroblasts, both responsible for collagen and proteoglycan production, further contributes to the tissue repair process.42 In physiological conditions, fibrocytes are not abundantly present in the arterial wall. However, in pathologic states, such as in hypertension,43,44 fibrocytes are recruited from the circulation through chemotactic ligand–receptor interactions to the injured tissue. During hypertension, resident fibrocyte hypertrophy and hyperplasia have also been described.45,46 Collagen accumulation and extracellular matrix reorganization, affected by resident fibrocytes, are also important factors that contribute to vessel wall stiffness and hypertension.43 In an experimental study of Ang-II-induced hypertension rodent model, fibrocytes played a pivotal role in the generation of vascular fibrosis through an increase in type I collagen production.44 Also, in pudendal arteries from SHR, an increase in fibrocyte markers was related to vascular dysfunction and erectile dysfunction.47 However, it is still controversial if circulating or resident fibrocytes play a major role in hypertension. For instance, little is known about how vascular resident fibrocytes contribute to the initial process of vascular remodeling. Furthermore, the suppressive effect of certain proinflammatory cytokines on fibrocyte formation and the role of this regulation in the development of vascular dysfunction is still not understood. TUNICA EXTERNA Fibroblasts Fibroblasts are the most abundant cell type within the tunica externa and key regulators of vascular wall structure and function.48 In vessels from normotensive rats, fibroblasts have a fusiform or polygonal morphology and have structural, secretory, and communicative (i.e., cell-to-cell interaction control) functions. Fibroblasts secrete growth factors, chemokines, and cytokines, which help control vascular function,49 elements of the extracellular matrix and aid in the degradation of extracellular matrix components. Fibroblasts are considered the principal cells for vascular remodeling in response to injury.50 However, during hypertension, fibroblasts undergo a morphological change that is accompanied with proliferation and migration into the tunica media.51 This response to injury also leads to the generation of chemokines, cytokines, adhesion molecules, reactive oxygen species, and matrix metalloproteinases (Table 1), along with proliferation of the vasa vasorum, eventually resulting in irreversible functional and structural remodeling of the vessel wall.48 Pericytes Pericytes are described as perivascular cells that “wrap” around arterioles, precapillary arterioles, capillaries, postcapillary venules, and venules52 (Figure 2). The ratio of pericytes to endothelial cells varies depending on which organ they are located in. Pericytes are found in greater numbers in areas of tight endothelial barrier regulation and slow endothelial proliferation. These cells exhibit a variety of roles that include scaffolding, communication, mechanical contractile force transmission, anchoring sites, and both the inability and ability to regulate vascular diameter in capillaries.53 Figure 2. View largeDownload slide Identification of pericytes in mice renal medullary capillaries. Pericytes (arrow) wrapping around medullary renal capillaries. Nerve/glial antigen 2-NG2 (red) used as pericyte localization marker for immunofluorescence. Abbreviation: DAPI (blue), 4′,6-diamidino-2-phenylindole. Figure 2. View largeDownload slide Identification of pericytes in mice renal medullary capillaries. Pericytes (arrow) wrapping around medullary renal capillaries. Nerve/glial antigen 2-NG2 (red) used as pericyte localization marker for immunofluorescence. Abbreviation: DAPI (blue), 4′,6-diamidino-2-phenylindole. Current literature suggests that not all pericytes are the same, as they exhibit different morphology and function; cell shape may range from a flat to a round cell body, and cell processes range from (i) wrapping entirely around a vessel, (ii) laying unidirectional in parallel with the length of the vessel, and (iii) exhibiting short processes creating a satellite-like cell shape.52 These differences can be categorized into 3 subclasses based on pericytes location along the capillary bed.52,54 Pericytes found closer to arterioles tend to exhibit circumferential processes that wrap around vessels.52,54 These pericytes have been reported to have more alpha-smooth muscle actin expression and have the ability to contract.52 Pericytes found around capillary beds tend to exhibit processes that run parallel to the vessel and express less alpha-smooth muscle actin than the pericytes found closer to arterioles. Pericytes found closer to venules have more of a satellite cell shape and do not express alpha-smooth muscle actin; therefore, they do not contract.54–58 The loose definition of pericytes and the contradictory role of this class of cells may account for varying reports of pericytes being both contractile and noncontractile.54,58,59 Hypertension has been associated with both an increase and a decrease in pericyte numbers.60–64 In mice with Ang-II-induced hypertension, the number of pericytes in cerebral arteries is decreased, leading to blood–brain barrier disruption.60 In contrast, SHR show increased pericyte number within the brain microcirculation, specifically within the motor cortex and pons.61 In pulmonary arterial hypertension, pulmonary arteries from both human and mice exhibit an increased number of pericytes with associated fibrosis and membrane thickening, and these where found to contribute to endothelial dysfunction.62–64 This phenomenon was suggested to be location specific and occur in response to recruitment signals to stabilize vessels. PERIVASCULAR ADIPOSE TISSUE In 1991, Cassis and Soltis65 used rat aorta from male Sprague-Dawley with and without PVAT to measure isometric force. Norepinephrine-induced contraction was reduced in tissues with PVAT. This experiment provided the first evidence that PVAT could change the function of the vessel around which it resided and possessed vasoactive functions. Since the publication of this seminal paper, scientists have discovered the importance of PVAT in modifying vessel function in multiple species, including humans, and in multiple vessel types, from large-sized vessels (aorta) to resistance-sized vessels. A majority of the work, however, has been done in larger size vessels such as the thoracic aorta because for these vessels, PVAT is easily identified. Current work has been reviewed by multiple investigators, and we encourage you to read these important reviews.66–75 PVAT is composed of multiple different cell types and tissues, including adipocytes, different cell types in the stromal vascular fraction, including small vasculature that supplies cells within PVAT with nutrients, fibroblasts and immune cells, and potentially nerves that innervate PVAT. Adipocytes can be both brown and white, and all arteries do not have the same “type” of PVAT. In fact, in the rat, the thoracic aorta is brown fat, the superior mesenteric artery is a mix of brown and white, and PVAT around the small mesenteric resistance arteries and veins is white. As such, no finding on a particular PVAT is necessarily applicable to another PVAT. Because there is no barrier between PVAT and the vessel, communication (cross-talk) can occur between PVAT and the vessel it surrounds. The PVAT anticontractile effects are caused by the release of different factors, including adiponectin, hydrogen sulfide, nitric oxide, etc.75 PVAT also has procontractile effects, caused by the production of vasoactive, contractile adipokines (such as angiotensin-II), and other small molecules (Table 1).76 Thus, it is the balance of molecules released from PVAT, as well as the bidirectional cross-talk,77 that ultimately determines the overall contributions made by PVAT to vessel contractility. The PVAT anticontractile action is lost in hypertension.68,69 The forms in which this anticontractile nature has been lost include both genetic and experimental models, as well as in humans with essential hypertension, though more work has been in done in animal models of obesity because of the increased burden of fat. Immune cell infiltration and PVAT PVAT appears to be a harbor for immune cells, both in healthy and pathologic states. This idea was led by the work of Tomas Guzik, who discovered that the presence of T cells was essential to the development of Ang-II-induced hypertension and hypertension-associated vascular dysfunction.78 Additionally, atheroprotective IgM-producing B cells were observed in the aortic PVAT of mice.79 Eosinophils may also be key in regulating the normal PVAT anticontractile function,80 and follicular dendritic cells emerge from precursors that exist in the perivascular space.81 Just recently, the importance of T cells in hypertension, as recruited to the PVAT, in both Ang-II and DOCA-salt hypertension in mice, was called into question with the inability of multiple labs across the country to reproduce the previously observed protection of the Rag1 mice (lack T and B cells) from Ang-II-induced hypertension.82 In dysfunctional PVAT (e.g., hypertension), immune cell infiltration becomes more prominent. Infiltrating cells include macrophages, memory T cells, IL-10-producing FoxP3 + T regulatory cells, natural killer cells, and granulocytes.83 Immune cell infiltrates in the PVAT contribute to the low-grade inflammation seen in multiple cardiovascular diseases.84–87 For instance, in humans, an increased burden of aortic PVAT in cardiovascular disease was seen in the Framingham Heart Study.88 Unfortunately, no PVAT-specific markers have been found that would permit PVAT-specific interventions. It would be ideal to have a biomarker or agent that could potentially turn a “sick” PVAT into a “healthy” PVAT. HYPERTENSION-RELATED CHANGES IN SPECIAL CIRCULATIONS Renal circulation The role that the kidney plays in the development and maintenance of hypertension has been described for centuries.89 The introduction of the pressure-natriuresis hypothesis by Arthur Guyton et al.90 in the 1970s suggested that a modification to the kidney’s capacity for water and sodium excretion was required for the perpetuation of chronic elevation of intra-arterial pressure, whereby the equilibrium point for salt and water excretion was shifted to a higher blood pressure. While this remains a largely accepted notion, some controversy arises with studies suggesting independent control of blood pressure by predominately neural and vascular mechanisms.91–93 The far reaching and complex role of renal physiology in blood pressure regulation is outside of the scope of this mini-review. However, hypertension is also recognized as one of the most important causes of end-stage renal disease,94 and the pathogenesis of hypertensive renal disease remains an area of great research interest and debate. Kidney damage is a prominent feature in most experimental models of hypertension.95–97 Many of the structural and functional changes in the vasculature recognized as hallmarks of chronic hypertension have also been observed in the kidney and warrant special consideration as components of this pathogenesis remain unclear. Specifically, renal injury in hypertension is heterogeneously distributed to the juxtamedullary region and outer medulla as has been observed in SHR, Dahl salt-sensitive hypertensive rats, renovascular hypertension, and Ang-II-induced hypertension.98–101 This results from the greater pressure gradient across the afferent arteriole in the juxtamedullary region, adjacent to the large arcuate artery, in contrast to the gradual pressure reduction that occurs over the length of the vasculature in the superficial cortical regions, including the entire interlobular artery and its afferent arterioles.98 A landmark study by Mori et al.101 supports the concept that elevated arterial pressure itself is primarily responsible for this renal injury. Mori et al. used the servocontrol method to maintain normotensive perfusion pressure to 1 kidney while inducing systemic hypertension via Ang-II infusion and showed extensive juxtamedullary, glomerular, and outer medullary tubulointerstitial injury in the pressure-uncontrolled kidney; this was largely prevented in the pressure-controlled contralateral kidney despite exposure to high levels of Ang-II. The exact temporal and spatial relationships between vascular, glomerular, and tubular changes in hypertensive renal disease remain unclear. Afferent arteriolar wall hypertrophy and glomerular capillary collapse have been observed and correlated with reduced glomerular and tubular flow in SHR, suggesting a causal relationship between afferent arteriolopathy and tubular injury.102 Thickening of the interlobular artery has been shown with infiltration of lymphocytes, VSMC proliferation, and imbalance of collagen metabolism featuring increased synthesis and inhibition of breakdown leading to fibrosis.95,103 Changes in vascular function and morphology precede renal damage in SHR, further indicating their importance in the pathogenesis of hypertensive renal disease.99,104,105 Whether vascular dysfunction is present in the renal vasculature prior to observable morphologic changes is poorly understood. Both angiotensin receptor blockers and calcium channel blockers have been shown to reduce glomerular sclerosis and arteriolar wall thickening in experimental animals; however, if this is due to mechanisms beyond their blood pressure–lowering effects remains unclear.106–108 It is well established that chronic activation of the innate immune system contributes to both hypertension and kidney injury. Work in our laboratory has shown increased circulation of mitochondrial DNA in SHR6 with associated systemic inflammation and vascular dysfunction via formyl peptide receptor activation. These findings were reproduced in isolated intrarenal arteries of normotensive rats exposed to mitochondrial fragments and were not attenuated with thiazide diuretic treatment despite lowering blood pressure (unpublished data). The effects of inflammation and chronic immune system activation on the development of renal dysfunction in hypertension-associated dysfunction remain largely unclear and represent an exciting avenue for future study. Cerebral circulation Hypertension has devastating effects on the brain. It is the leading cause of stroke and a major cause of dementia and cognitive impairment. The cerebral vasculature has several important structural and functional differences from the peripheral circulation, which serve to maintain continuous perfusion. Surface pial arteries form an effective collateral network, and occlusion of a single vessel does not significantly reduce cerebral blood flow. However, downstream-penetrating and parenchymal arterioles are largely unbranched, and a single-vessel occlusion can significantly reduce blood flow and result in ischemia.109Table 2 summarizes several important structural and functional changes in cerebral arteries during hypertension. Table 2. Summary of hypertension-associated dysfunction in cerebral arteries Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Abbreviation: ACEI, angiotensin converting enzyme inhibitors; SHR, spontaneously hypertensive rats. View Large Table 2. Summary of hypertension-associated dysfunction in cerebral arteries Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Vessel type  Location  Unique characteristics  Hypertension-associated dysfunction  Pial arteries  Surface (leptomeninges)  Extrinsic (peripheral) and intrinsic (central) perivascular innervation  Impaired vasodilation in response to ischemia in SHR compared with normotensive rat120      Effective collateral  Impaired collateral growth in SHR after carotid occlusion restored with antihypertensive treatment121      2–3 layers smooth muscle cells    Penetrating arterioles  Virchow–Robin space  Single layer smooth muscle with increased basal tone and unresponsiveness to some neurotransmitters122  Remodeling observed (increased wall thickness and reduction of lumen diameter)123      Poor collateral  ACEI can reverse remodeling124  Parenchymal arterioles  Completely surrounded by astrocytic end-feet  Single layer of smooth muscle cells arranged circularly perpendicular to flow  Rarefaction in hypertension contributes to increased resistance125        Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension.  Capillaries  Surrounded by pericytes and basal lamina (continuous with astrocytic end-feet)  Nearly 1:1 ratio with neurons  Rarefaction in hypertension contributes to increased resistance125      All capillaries perfused at all times  Loss associated with chronic hypoperfusion and increased risk of cognitive impairment and dementia in hypertension  Abbreviation: ACEI, angiotensin converting enzyme inhibitors; SHR, spontaneously hypertensive rats. View Large The effects of hypertension on the cerebral circulation are numerous and complex and have been reviewed extensively elsewhere.110,111 The deleterious effects of hypertension in the brain include vessel rarefaction, artery remodeling, and hypertrophy, changes in vascular myogenic reactivity, and endothelial dysfunction with compromise of the blood–brain barrier. Numerous cell types play a unique role in the cerebral circulation, and their role in hypertension is summarized in Table 3. Table 3. Summary of cell types involved in hypertension-associated dysfunction of the cerebral vasculature Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Abbreviations: BBB, blood–brain barrier; ICAM, intercellular adhesion molecule; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell. View Large Table 3. Summary of cell types involved in hypertension-associated dysfunction of the cerebral vasculature Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Cell Type  Location  Function  Role/dysfunction in hypertension  Endothelial cell  Tunica intima  BBB  Diminished NO bioavailability126      Endothelium-dependent dilation (NO dependent and independent mechanisms)  Endothelium-derived hyperpolarizing factor impairment127        Enhanced BBB permeability (increased ROS, TNF-α, IL-6, ICAM-1)128  VSMC  Tunica media  Myogenic reactivity  Altered cytoskeleton organization129      Vascular tone  Impaired contraction to potassium chloride  Astrocyte  Tunica adventitia  Role in barrier function via tight junction protein upregulation, flow regulation, ion homeostasis, and neuron interfacing  Astrocyte swelling and fibrosis observed in hypertension linked to loss of tight junctions and neuron cell death130  Pericyte  Capillary bed  Common basement membrane with endothelial cells  Granular pericytes activate and grow in size during development of hypertension      Secrete growth factors and extracellular matrix proteins  Filamentous pericytes degenerate with associated increased endothelial permeability130      Important for remodeling and angiogenesis131    Perivascular macrophage  Tunica adventitia  Key component of brain resident immune system  Mediate neurovascular, cognitive dysfunction, and cerebrovascular remodeling induced by hypertension132  Abbreviations: BBB, blood–brain barrier; ICAM, intercellular adhesion molecule; IL, interleukin; NO, nitric oxide; ROS, reactive oxygen species; TNF, tumor necrosis factor; VSMC, vascular smooth muscle cell. View Large Hepatic circulation The liver receives one-third of its blood supply from the hepatic artery and the remaining two-thirds from the portal vein. Its immense vascularization is highlighted by the fact that it receives 25% of cardiac output despite only comprising 2% of body weight. This is accomplished by a pressure gradient of only a few millimeters of mercury. Due to extremely distensible capacitance and venous resistance sites, the liver plays a crucial role in response to decreased or increased blood volume and has a recognized role in determining the response to vasopressors, antihypertensives, and afterload-reducing agents.112 Essential hypertension is strongly linked to the development of nonalcoholic fatty liver disease.113 Both, nonalcoholic fatty liver disease and hypertension are well-established components of metabolic syndrome, and their relationship appears to be related to increased insulin resistance and total body weight.114 Hypertension is also associated with nonalcoholic fatty liver disease independent of body mass, highlighting the importance of evaluating hypertensive patients for the development of liver disease and vice versa.115 Interestingly, patients with hypertension are likely to become normotensive as cirrhosis develops, and hypertension is rarely manifested in patients with established cirrhosis.116 This is likely due to an overall vasodilatory state in cirrhosis mediated through complex, interconnected mechanisms including adrenomedullin, calcitonin gene-related peptide, nitric oxide, and other vasodilators present in the splanchnic vascular bed.116 The above observations highlight the complex role of the hepatic circulation in altering systemic hemodynamics in both the healthy and pathologic states. CONCLUSION Vascular dysfunction is undoubtedly associated with the genesis and/or maintenance of hypertension. Although endothelial cells and VSMCs dysfunction are the most commonly associated culprit for the vascular changes seen in hypertension, evidence shows that other cell types within the vasculature are also involved in this phenomenon (summarized in Figure 3a,b). Unfortunately, specific markers and/or pharmacological agents that are able to differentiate cells for specific interventions are limited or simply do not exist. It is of critical importance to understand the basic physiologic role of each cell type within the vasculature and identify their contributions to the development of vascular dysfunction in hopes that new targeted therapies can be produced. Figure 3. View largeDownload slide Representative images comparing vascular changes between resistance arteries from normotensive (a) and hypertensive (b) model. When comparing hypertensive resistance arteries with normotensive ones, it is important to note that endothelial cells are damaged and express adhesion molecules, VSMC hypertrophy and hyperplasia, increase in number of infiltrating cells between the medial layer and adventitial layer, increased collagen deposition, and increased number of resident fibrocytes. Figure 3. View largeDownload slide Representative images comparing vascular changes between resistance arteries from normotensive (a) and hypertensive (b) model. When comparing hypertensive resistance arteries with normotensive ones, it is important to note that endothelial cells are damaged and express adhesion molecules, VSMC hypertrophy and hyperplasia, increase in number of infiltrating cells between the medial layer and adventitial layer, increased collagen deposition, and increased number of resident fibrocytes. ACKNOWLEDGMENTS We would like to acknowledge Drs O’Connor and Crislip from the Department of Physiology at Augusta University, who kindly provided Figure 2 for this manuscript. We also would like to thank Lynsey Ekema, MSMI, for her artistic contribution to our Figure 3a,b. The work is funded by NIH through grant numbers P01 HL134604 and 1K99GM118885-01. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA, Williamson JD, Wright JT. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/ PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults . A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, 2017. 2. Fry DL. Acute vascular endothelial changes associated with increased blood velocity gradients. Circ Res  1968; 22: 165– 197. Google Scholar CrossRef Search ADS PubMed  3. Fry DL. Certain histological and chemical responses of the vascular interface to acutely induced mechanical stress in the aorta of the dog. Circ Res  1969; 24: 93– 108. Google Scholar CrossRef Search ADS PubMed  4. Vaziri ND, Ni Z, Oveisi F. Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats. Hypertension  1998; 31: 1248– 1254. Google Scholar CrossRef Search ADS PubMed  5. Wenceslau CF, McCarthy CG, Szasz T, Goulopoulou S, Webb RC. Mitochondrial N-formyl peptides induce cardiovascular collapse and sepsis-like syndrome. Am J Physiol Heart Circ Physiol  2015; 308: H768– H777. Google Scholar CrossRef Search ADS PubMed  6. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC, Matsumoto T, Webb RC. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res  2015; 107: 119– 130. Google Scholar CrossRef Search ADS PubMed  7. Schmid-Schoenbein GW, Fung YC, Zweifach BW. Vascular endothelium-leukocyte interaction; sticking shear force in venules. Circ Res  1975; 36: 173– 184. Google Scholar CrossRef Search ADS PubMed  8. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension  2014; 63: 572– 579. Google Scholar CrossRef Search ADS PubMed  9. Kirsch T, Beese M, Wyss K, Klinge U, Haller H, Haubitz M, Fiebeler A. Aldosterone modulates endothelial permeability and endothelial nitric oxide synthase activity by rearrangement of the actin cytoskeleton. Hypertension  2013; 61: 501– 508. Google Scholar CrossRef Search ADS PubMed  10. Hall A. Rho GTPases and the actin cytoskeleton. Science  1998; 279: 509– 514. Google Scholar CrossRef Search ADS PubMed  11. Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol  2013; 62: 341– 354. Google Scholar CrossRef Search ADS PubMed  12. Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci  2016; 73: 57– 77. Google Scholar CrossRef Search ADS PubMed  13. Mehta D, Ravindran K, Kuebler WM. Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol  2014; 307: L924– L935. Google Scholar CrossRef Search ADS PubMed  14. Pitas RE, Boyles J, Mahley RW, Bissell DM. Uptake of chemically modified low density lipoproteins in vivo is mediated by specific endothelial cells. J Cell Biol  1985; 100: 103– 117. Google Scholar CrossRef Search ADS PubMed  15. Piper PJ, Vane JR, Wyllie JH. Inactivation of prostaglandins by the lungs. Nature  1970; 225: 600– 604. Google Scholar CrossRef Search ADS PubMed  16. Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB-mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun  1995; 209: 483– 489. Google Scholar CrossRef Search ADS PubMed  17. Jeffery TK, Bryan-Lluka LJ, Wanstall JC. Specific uptake of 5-hydroxytryptamine is reduced in lungs from hypoxic pulmonary hypertensive rats. Eur J Pharmacol  2000; 396: 137– 140. Google Scholar CrossRef Search ADS PubMed  18. Vanhoutte PM. Serotonin and the blood-vessel wall. J Hypertens Suppl  1986; 4: S112– S115. Google Scholar PubMed  19. Pucovský V. Interstitial cells of blood vessels. ScientificWorldJournal  2010; 10: 1152– 1168. Google Scholar CrossRef Search ADS PubMed  20. Pucovsky V, Moss RF, Bolton TB. Non-contractile cells with thin processes resembling interstitial cells of Cajal found in the wall of guinea-pig mesenteric arteries. J Physiol  2003; 552: 119– 133. Google Scholar CrossRef Search ADS PubMed  21. Harhun MI, Szewczyk K, Laux H, Prestwich SA, Gordienko DV, Moss RF, Bolton TB. Interstitial cells from rat middle cerebral artery belong to smooth muscle cell type. J Cell Mol Med  2009; 13: 4532– 4539. Google Scholar CrossRef Search ADS PubMed  22. Povstyan OV, Gordienko DV, Harhun MI, Bolton TB. Identification of interstitial cells of Cajal in the rabbit portal vein. Cell Calcium  2003; 33: 223– 239. Google Scholar CrossRef Search ADS PubMed  23. Harhun MI, Pucovský V, Povstyan OV, Gordienko DV, Bolton TB. Interstitial cells in the vasculature. J Cell Mol Med  2005; 9: 232– 243. Google Scholar CrossRef Search ADS PubMed  24. Bobryshev YV. Subset of cells immunopositive for neurokinin-1 receptor identified as arterial interstitial cells of Cajal in human large arteries. Cell Tissue Res  2005; 321: 45– 55. Google Scholar CrossRef Search ADS PubMed  25. Ghose D, L J, Manjunatha S, MS R, Rao JP. Inherent rhythmicity and interstitial cells of Cajal in a frog vein. J Biosci  2008; 33: 755– 759. Google Scholar CrossRef Search ADS PubMed  26. Morel E, Meyronet D, Thivolet-Bejuy F, Chevalier P. Identification and distribution of interstitial Cajal cells in human pulmonary veins. Heart Rhythm  2008; 5: 1063– 1067. Google Scholar CrossRef Search ADS PubMed  27. Bolton TB, Gordienko DV, Povstyan OV, Harhun MI, Pucovsky V. Smooth muscle cells and interstitial cells of blood vessels. Cell Calcium  2004; 35: 643– 657. Google Scholar CrossRef Search ADS PubMed  28. Lou Z, Li JS. Interstitial cells of Cajal in abdominal sepsis and hypertension-induced ileus in rats. Eur Surg Res  2009; 43: 47– 52. Google Scholar CrossRef Search ADS PubMed  29. Pauly RR, Passaniti A, Bilato C, Monticone R, Cheng L, Papadopoulos N, Gluzband YA, Smith L, Weinstein C, Lakatta EG. Migration of cultured vascular smooth muscle cells through a basement membrane barrier requires type IV collagenase activity and is inhibited by cellular differentiation. Circ Res  1994; 75: 41– 54. Google Scholar CrossRef Search ADS PubMed  30. Szasz T, Tostes RCA. Vascular smooth muscle function in hypertension. Colloquium Series on Integrated Systems Physiology: From Molecule to Function . 2016; 8: i– 96. 31. Mulvany MJ. Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res  1999; 41: 9– 13. Google Scholar CrossRef Search ADS PubMed  32. Mulvany MJ. Small artery remodelling in hypertension. Basic Clin Pharmacol Toxicol  2012; 110: 49– 55. Google Scholar CrossRef Search ADS PubMed  33. Folkow B, Grimby G, Thulesius O. Adaptive structural changes of the vascular walls in hypertension and their relation to the control of the peripheral resistance. Acta Physiol Scand  1958; 44: 255– 272. Google Scholar CrossRef Search ADS PubMed  34. Castorena-Gonzalez JA, Staiculescu MC, Foote C, Martinez-Lemus LA. Mechanisms of the inward remodeling process in resistance vessels: is the actin cytoskeleton involved? Microcirculation  2014; 21: 219– 229. Google Scholar CrossRef Search ADS PubMed  35. Hadrava V, Kruppa U, Russo RC, Lacourcière Y, Tremblay J, Hamet P. Vascular smooth muscle cell proliferation and its therapeutic modulation in hypertension. Am Heart J  1991; 122: 1198– 1203. Google Scholar CrossRef Search ADS PubMed  36. Cipolla MJ, Gokina NI, Osol G. Pressure-induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J  2002; 16: 72– 76. Google Scholar CrossRef Search ADS PubMed  37. Staiculescu MC, Galiñanes EL, Zhao G, Ulloa U, Jin M, Beig MI, Meininger GA, Martinez-Lemus LA. Prolonged vasoconstriction of resistance arteries involves vascular smooth muscle actin polymerization leading to inward remodelling. Cardiovasc Res  2013; 98: 428– 436. Google Scholar CrossRef Search ADS PubMed  38. Yamin R, Morgan KG. Deciphering actin cytoskeletal function in the contractile vascular smooth muscle cell. J Physiol  2012; 590: 4145– 4154. Google Scholar CrossRef Search ADS PubMed  39. Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med  1994; 1: 71– 81. Google Scholar PubMed  40. Li J, Tan H, Wang X, Li Y, Samuelson L, Li X, Cui C, Gerber DA. Circulating fibrocytes stabilize blood vessels during angiogenesis in a paracrine manner. Am J Pathol  2014; 184: 556– 571. Google Scholar CrossRef Search ADS PubMed  41. Reilkoff RA, R B, Herzog EL. Fibrocytes: emerging effector cells in chronic inflammation. Nat Rev Immunol  2011; 11: 427– 435. Google Scholar CrossRef Search ADS PubMed  42. Rios FJ, Harvey A, Lopes RA, Montezano AC, Touyz RM. Progenitor cells, bone marrow-derived fibrocytes and endothelial-to-mesenchymal transition: new players in vascular fibrosis. Hypertension  2016; 67: 272– 274. Google Scholar PubMed  43. Safar ME. Arterial stiffness as a risk factor for clinical hypertension. Nat Rev Cardiol  2017. 44. Wu J, Montaniel KR, Saleh MA, Xiao L, Chen W, Owens GK, Humphrey JD, Majesky MW, Paik DT, Hatzopoulos AK, Madhur MS, Harrison DG. Origin of matrix-producing cells that contribute to aortic fibrosis in hypertension. Hypertension  2016; 67: 461– 468. Google Scholar PubMed  45. Andersson-Sjöland A, Erjefält JS, Bjermer L, Eriksson L, Westergren-Thorsson G. Fibrocytes are associated with vascular and parenchymal remodelling in patients with obliterative bronchiolitis. Respir Res  2009; 10: 103. Google Scholar CrossRef Search ADS PubMed  46. Medbury HJ, Tarran SL, Guiffre AK, Williams MM, Lam TH, Vicaretti M, Fletcher JP. Monocytes contribute to the atherosclerotic cap by transformation into fibrocytes. Int Angiol  2008; 27: 114– 123. Google Scholar PubMed  47. Ogbi S, Webb RC. Fibrocyte markers are increased in pudendal artery of spontaneously hypertensive rats (SHR). FASEB J  2016; 30: lb617. 48. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol  2013; 75: 23– 47. Google Scholar CrossRef Search ADS PubMed  49. Sorrell JM, Caplan AI. Fibroblasts-a diverse population at the center of it all. Int Rev Cell Mol Biol  2009; 276: 161– 214. Google Scholar CrossRef Search ADS PubMed  50. Yuan W, Liu W, Li J, Li X, Sun X, Xu F, Man X, Fu Q. Effects of BMSCs interactions with adventitial fibroblasts in transdifferentiation and ultrastructure processes. Int J Clin Exp Pathol  2014; 7: 3957– 3965. Google Scholar PubMed  51. McGrath JC, Deighan C, Briones AM, Shafaroudi MM, McBride M, Adler J, Arribas SM, Vila E, Daly CJ. New aspects of vascular remodelling: the involvement of all vascular cell types. Exp Physiol  2005; 90: 469– 475. Google Scholar CrossRef Search ADS PubMed  52. Armulik A, Genové G, Betsholtz C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell  2011; 21: 193– 215. Google Scholar CrossRef Search ADS PubMed  53. van Dijk CG, Nieuweboer FE, Pei JY, Xu YJ, Burgisser P, van Mulligen E, el Azzouzi H, Duncker DJ, Verhaar MC, Cheng C. The complex mural cell: pericyte function in health and disease. Int J Cardiol  2015; 190: 75– 89. Google Scholar CrossRef Search ADS PubMed  54. Attwell D, Mishra A, Hall CN, O’Farrell FM, Dalkara T. What is a pericyte? J Cereb Blood Flow Metab  2016; 36: 451– 455. 55. Hartmann DA, Underly RG, Grant RI, Watson AN, Lindner V, Shih AY. Pericyte structure and distribution in the cerebral cortex revealed by high-resolution imaging of transgenic mice. Neurophotonics  2015; 2: 041402. Google Scholar CrossRef Search ADS PubMed  56. Fernández-Klett F, Priller J. Diverse functions of pericytes in cerebral blood flow regulation and ischemia. J Cereb Blood Flow Metab  2015; 35: 883– 887. Google Scholar CrossRef Search ADS PubMed  57. Dore-Duffy P, Cleary K. Morphology and properties of pericytes. Methods Mol Biol  2011; 686: 49– 68. Google Scholar CrossRef Search ADS PubMed  58. Zimmermann KW. Der Feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch  1923; 68: 29– 109. Google Scholar CrossRef Search ADS   59. Krueger M, Bechmann I. CNS pericytes: concepts, misconceptions, and a way out. Glia  2010; 58: 1– 10. Google Scholar CrossRef Search ADS PubMed  60. Toth P, Tucsek Z, Sosnowska D, Gautam T, Mitschelen M, Tarantini S, Deak F, Koller A, Sonntag WE, Csiszar A, Ungvari Z. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab  2013; 33: 1732– 1742. Google Scholar CrossRef Search ADS PubMed  61. Herman IM, Jacobson S. In situ analysis of microvascular pericytes in hypertensive rat brains. Tissue Cell  1988; 20: 1– 12. Google Scholar CrossRef Search ADS PubMed  62. Yuan K, Shao NY, Hennigs JK, Discipulo M, Orcholski ME, Shamskhou E, Richter A, Hu X, Wu JC, de Jesus Perez VA. Increased pyruvate dehydrogenase kinase 4 expression in lung pericytes is associated with reduced endothelial-pericyte interactions and small vessel loss in pulmonary arterial hypertension. Am J Pathol  2016; 186: 2500– 2514. Google Scholar CrossRef Search ADS PubMed  63. Wang S, Zeng H, Xie XJ, Tao YK, He X, Roman RJ, Aschner JL, Chen JX. Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget  2016; 7: 58848– 58861. Google Scholar PubMed  64. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmüller P, Humbert M, Guignabert C. Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation  2014; 129: 1586– 1597. Google Scholar CrossRef Search ADS PubMed  65. Soltis EE, Cassis LA. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A  1991; 13: 277– 296. Google Scholar PubMed  66. Aghamohammadzadeh R, Heagerty AM. Obesity-related hypertension: epidemiology, pathophysiology, treatments, and the contribution of perivascular adipose tissue. Ann Med  2012; 44: S74– 84. Google Scholar CrossRef Search ADS PubMed  67. Aghamohammadzadeh R, Withers S, Lynch F, Greenstein A, Malik R, Heagerty A. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Br J Pharmacol  2012; 165: 670– 682. Google Scholar CrossRef Search ADS PubMed  68. Akoumianakis I, Tarun A, Antoniades C. Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets. Br J Pharmacol  2017; 174: 3411– 3424. Google Scholar CrossRef Search ADS PubMed  69. Brandes RP. The fatter the better? Perivascular adipose tissue attenuates vascular contraction through different mechanisms. Br J Pharmacol  2007; 151: 303– 304. Google Scholar CrossRef Search ADS PubMed  70. Chaldakov GN, Fiore M, Ghenev PI, Beltowski J, Ranćić G, Tunçel N, Aloe L. Triactome: neuro-immune-adipose interactions. Implication in vascular biology. Front Immunol  2014; 5: 130. Google Scholar CrossRef Search ADS PubMed  71. Chaldakov GN, Fiore M, Rancic G, Gehenev P, Tuncel N, Beltowski Jet al.   Rethinking vascular wall: periadventitial adipose tissue (tunica adiposa). Obes Metab  2010; 6: 46– 9. 72. Eringa EC, Bakker W, van Hinsbergh VW. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. Vascul Pharmacol  2012; 58: 204– 209. Google Scholar CrossRef Search ADS   73. Gollasch M, Dubrovska G. Paracrine role for periadventitial adipose tissue in the regulation of arterial tone. Trends Pharmacol Sci  2004; 25: 647– 653. Google Scholar CrossRef Search ADS PubMed  74. Kennedy S, Salt IP. Molecular mechanisms regulating perivascular adipose tissue—potential pharmacological targets? Br J Pharmacol  2017; 174: 3385– 3387. Google Scholar CrossRef Search ADS PubMed  75. Szasz T, Webb RC. Perivascular adipose tissue: more than just structural support. Clin Sci (Lond)  2012; 122: 1– 12. Google Scholar CrossRef Search ADS PubMed  76. Ramirez JG, O’Malley EJ, Ho WSV. Pro-contractile effects of perivascular fat in health and disease. Br J Pharmacol  2017; 2017: 20. 77. Rajsheker S, Manka D, Blomkalns AL, Chatterjee TK, Stoll LL, Weintraub NL. Crosstalk between perivascular adipose tissue and blood vessels. Curr Opin Pharmacol  2010; 10: 191– 196. Google Scholar CrossRef Search ADS PubMed  78. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med  2007; 204: 2449– 2460. Google Scholar CrossRef Search ADS PubMed  79. Srikakulapu P, Upadhye A, Rosenfeld SM, Marshall MA, McSkimming C, Hickman AW, Mauldin IS, Ailawadi G, Lopes MBS, Taylor AM, McNamara CA. Perivascular adipose tissue harbors atheroprotective IgM-producing B cells. Front Physiol  2017; 8: 719. Google Scholar CrossRef Search ADS PubMed  80. Withers SB, Forman R, Meza-Perez S, Sorobetea D, Sitnik K, Hopwood T, Lawrence CB, Agace WW, Else KJ, Heagerty AM, Svensson-Frej M, Cruickshank SM. Eosinophils are key regulators of perivascular adipose tissue and vascular functionality. Sci Rep  2017; 7: 44571. Google Scholar CrossRef Search ADS PubMed  81. Krautler NJ, Kana V, Kranich J, Tian Y, Perera D, Lemm D, Schwarz P, Armulik A, Browning JL, Tallquist M, Buch T, Oliveira-Martins JB, Zhu C, Hermann M, Wagner U, Brink R, Heikenwalder M, Aguzzi A. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell  2012; 150: 194– 206. Google Scholar CrossRef Search ADS PubMed  82. Ji H, Pai AV, West CA, Wu X, Speth RC, Sandberg K. Loss of resistance to angiotensin II-induced hypertension in the Jackson laboratory recombination-activating gene null mouse on the C57BL/6J background. Hypertension  2017; 69: 1121– 1127. Google Scholar CrossRef Search ADS PubMed  83. Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating immune cells in dysfunctional adipose tissue. Cardiovasc Res  2017; 113: 1009– 1023. Google Scholar CrossRef Search ADS PubMed  84. Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res  2012; 110: 889– 900. Google Scholar CrossRef Search ADS PubMed  85. Fernández-Alfonso MS, Gil-Ortega M, Aranguez I, Souza D, Dreifaldt M, Somoza B, Dashwood MR. Role of PVAT in coronary atherosclerosis and vein graft patency: friend or foe? Br J Pharmacol  2017; 174: 3561– 3572. Google Scholar CrossRef Search ADS PubMed  86. Mikolajczyk TP, Nosalski R, Szczepaniak P, Budzyn K, Osmenda G, Skiba D, Sagan A, Wu J, Vinh A, Marvar PJ, Guzik B, Podolec J, Drummond G, Lob HE, Harrison DG, Guzik TJ. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. FASEB J  2016; 30: 1987– 1999. Google Scholar CrossRef Search ADS PubMed  87. Nosalski R, Guzik TJ. Perivascular adipose tissue inflammation in vascular disease. Br J Pharmacol  2017; 174: 3496– 3513. Google Scholar CrossRef Search ADS PubMed  88. CS BKF. Ectopic fat deposits and cardiovascular disease. Circulation  2011; 124: e837– e41. CrossRef Search ADS PubMed  89. Coffman TM. The inextricable role of the kidney in hypertension. J Clin Invest  2014; 124: 2341– 2347. Google Scholar CrossRef Search ADS PubMed  90. Guyton AC, Coleman TG, Cowley AVJr, Scheel KW, Manning RDJr, Norman RAJr. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med  1972; 52: 584– 594. Google Scholar CrossRef Search ADS PubMed  91. McCurley A, Pires PW, Bender SB, Aronovitz M, Zhao MJ, Metzger D, Chambon P, Hill MA, Dorrance AM, Mendelsohn ME, Jaffe IZ. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med  2012; 18: 1429– 1433. Google Scholar CrossRef Search ADS PubMed  92. Michael SK, Surks HK, Wang Y, Zhu Y, Blanton R, Jamnongjit M, Aronovitz M, Baur W, Ohtani K, Wilkerson MK, Bonev AD, Nelson MT, Karas RH, Mendelsohn ME. High blood pressure arising from a defect in vascular function. Proc Natl Acad Sci USA  2008; 105: 6702– 6707. Google Scholar CrossRef Search ADS PubMed  93. Osborn JW, Fink GD, Kuroki MT. Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation. Curr Hypertens Rep  2011; 13: 221– 228. Google Scholar CrossRef Search ADS PubMed  94. Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani A, Kasiske B, Liu J, Mau LW, McBean M, Murray A, St Peter W, Guo H, Gustafson S, Li Q, Li S, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L. US Renal Data System 2010 Annual Data Report. Am J Kidney Dis  2011; 57: A8, e1– A8, 526. Google Scholar CrossRef Search ADS   95. Hultström M, Leh S, Skogstrand T, Iversen BM. Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage. Nephrol Dial Transplant  2008; 23: 896– 903. Google Scholar CrossRef Search ADS PubMed  96. Ochodnický P, Henning RH, Buikema HJ, de Zeeuw D, Provoost AP, van Dokkum RP. Renal vascular dysfunction precedes the development of renal damage in the hypertensive Fawn-Hooded rat. Am J Physiol Renal Physiol  2010; 298: F625– F633. Google Scholar CrossRef Search ADS PubMed  97. Skogstrand T, Leh S, Paliege A, Reed RK, Vikse BE, Bachmann S, Iversen BM, Hultström M. Arterial damage precedes the development of interstitial damage in the nonclipped kidney of two-kidney, one-clip hypertensive rats. J Hypertens  2013; 31: 152– 159. Google Scholar CrossRef Search ADS PubMed  98. Ito S, Nagasawa T, Abe M, Mori T. Strain vessel hypothesis: a viewpoint for linkage of albuminuria and cerebro-cardiovascular risk. Hypertens Res  2009; 32: 115– 121. Google Scholar CrossRef Search ADS PubMed  99. Iversen BM, Amann K, Kvam FI, Wang X, Ofstad J. Increased glomerular capillary pressure and size mediate glomerulosclerosis in SHR juxtamedullary cortex. Am J Physiol  1998; 274: F365– F373. Google Scholar CrossRef Search ADS PubMed  100. Johnson RJ, Gordon KL, Giachelli C, Kurth T, Skelton MM, Cowley AWJr. Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS rat. J Hypertens  2000; 18: 1497– 1505. Google Scholar CrossRef Search ADS PubMed  101. Mori T, Cowley AWJr. Role of pressure in angiotensin II-induced renal injury: chronic servo-control of renal perfusion pressure in rats. Hypertension  2004; 43: 752– 759. Google Scholar CrossRef Search ADS PubMed  102. Leh S, Hultström M, Rosenberger C, Iversen BM. Afferent arteriolopathy and glomerular collapse but not segmental sclerosis induce tubular atrophy in old spontaneously hypertensive rats. Virchows Arch  2011; 459: 99– 108. Google Scholar CrossRef Search ADS PubMed  103. Ofstad J, Iversen BM. Glomerular and tubular damage in normotensive and hypertensive rats. Am J Physiol Renal Physiol  2005; 288: F665– F672. Google Scholar CrossRef Search ADS PubMed  104. Kimura K, Nanba S, Tojo A, Hirata Y, Matsuoka H, Sugimoto T. Variations in arterioles in spontaneously hypertensive rats. Morphometric analysis of afferent and efferent arterioles. Virchows Arch A Pathol Anat Histopathol  1989; 415: 565– 569. Google Scholar CrossRef Search ADS PubMed  105. Skov K, Mulvany MJ. Structure of renal afferent arterioles in the pathogenesis of hypertension. Acta Physiol Scand  2004; 181: 397– 405. Google Scholar CrossRef Search ADS PubMed  106. Aoki Y, Kai H, Kajimoto H, Kudo H, Takayama N, Yasuoka S, Anegawa T, Iwamoto Y, Uchiwa H, Fukuda K, Kage M, Kato S, Fukumoto Y, Imaizumi T. Large blood pressure variability aggravates arteriolosclerosis and cortical sclerotic changes in the kidney in hypertensive rats. Circ J  2014; 78: 2284– 2291. Google Scholar CrossRef Search ADS PubMed  107. Aritomi S, Koganei H, Wagatsuma H, Mitsui A, Ogawa T, Nitta K, Konda T. The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet. Heart Vessels  2010; 25: 549– 555. Google Scholar CrossRef Search ADS PubMed  108. Eliahou H, Avinoach I, Shahmurov M, Ben-David A, Shahar C, Matas Z, Zimlichman R. Renoprotective effect of angiotensin II receptor antagonists in experimental chronic renal failure. Am J Nephrol  2001; 21: 78– 83. Google Scholar CrossRef Search ADS PubMed  109. Nishimura N, Schaffer CB, Friedman B, Lyden PD, Kleinfeld D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci USA  2007; 104: 365– 370. Google Scholar CrossRef Search ADS PubMed  110. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol  2013; 304: H1598– H1614. Google Scholar CrossRef Search ADS PubMed  111. Iadecola C, Davisson RL. Hypertension and cerebrovascular dysfunction. Cell Metab  2008; 7: 476– 484. Google Scholar CrossRef Search ADS PubMed  112. Lautt WW. Hepatic circulation: physiology and pathophysiology. In CTI - Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease , Morgan & Claypool Life Sciences, 2009. Google Scholar CrossRef Search ADS   113. Brookes MJ, Cooper BT. Hypertension and fatty liver: guilty by association? J Hum Hypertens  2007; 21: 264– 270. Google Scholar CrossRef Search ADS PubMed  114. Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, Bolondi L. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut  2004; 53: 1020– 1023. Google Scholar CrossRef Search ADS PubMed  115. Michopoulos S, Chouzouri VI, Manios ED, Grapsa E, Antoniou Z, Papadimitriou CA, Zakopoulos N, Dimopoulos AM. Untreated newly diagnosed essential hypertension is associated with nonalcoholic fatty liver disease in a population of a hypertensive center. Clin Exp Gastroenterol  2016; 9: 1– 9. Google Scholar CrossRef Search ADS PubMed  116. Henriksen JH, Moller S. Liver cirrhosis and arterial hypertension. World J Gastroenterol  2006; 12: 678– 685. Google Scholar CrossRef Search ADS PubMed  117. Klee NS, McCarthy CG, Martinez-Quinones P, Webb RC. Out of the frying pan and into the fire: damage-associated molecular patterns and cardiovascular toxicity following cancer therapy. Ther Adv Cardiovasc Dis  2017; 11: 297– 317. Google Scholar CrossRef Search ADS PubMed  118. Kapustin AN, Chatrou ML, Drozdov I, Zheng Y, Davidson SM, Soong D, Furmanik M, Sanchis P, De Rosales RT, Alvarez-Hernandez D, Shroff R, Yin X, Muller K, Skepper JN, Mayr M, Reutelingsperger CP, Chester A, Bertazzo S, Schurgers LJ, Shanahan CM. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res  2015; 116: 1312– 1323. Google Scholar CrossRef Search ADS PubMed  119. Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, Kaneko S. Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA  2006; 103: 14098– 14103. Google Scholar CrossRef Search ADS PubMed  120. Coyle P, Heistad DD. Blood flow through cerebral collateral vessels in hypertensive and normotensive rats. Hypertension  1986; 8: Ii67– Ii 71. Google Scholar CrossRef Search ADS PubMed  121. Omura-Matsuoka E, Yagita Y, Sasaki T, Terasaki Y, Oyama N, Sugiyama Y, Todo K, Sakoda S, Kitagawa K. Hypertension impairs leptomeningeal collateral growth after common carotid artery occlusion: restoration by antihypertensive treatment. J Neurosci Res  2011; 89: 108– 116. Google Scholar CrossRef Search ADS PubMed  122. Cipolla MJ, Li R, Vitullo L. Perivascular innervation of penetrating brain parenchymal arterioles. J Cardiovasc Pharmacol  2004; 44: 1– 8. Google Scholar CrossRef Search ADS PubMed  123. Mulvany MJ. Small artery remodeling and significance in the development of hypertension. News Physiol Sci  2002; 17: 105– 109. Google Scholar PubMed  124. Dupuis F, Atkinson J, Limiñana P, Chillon JM. Captopril improves cerebrovascular structure and function in old hypertensive rats. Br J Pharmacol  2005; 144: 349– 356. Google Scholar CrossRef Search ADS PubMed  125. Sokolova IA, Manukhina EB, Blinkov SM, Koshelev VB, Pinelis VG, Rodionov IM. Rarefication of the arterioles and capillary network in the brain of rats with different forms of hypertension. Microvasc Res  1985; 30: 1– 9. Google Scholar CrossRef Search ADS PubMed  126. Miller AA, Budzyn K, Sobey CG. Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention. Clin Sci (Lond)  2010; 119: 1– 17. Google Scholar CrossRef Search ADS PubMed  127. Giachini FR, Carneiro FS, Lima VV, Carneiro ZN, Dorrance A, Webb RC, Tostes RC. Upregulation of intermediate calcium-activated potassium channels counterbalance the impaired endothelium-dependent vasodilation in stroke-prone spontaneously hypertensive rats. Transl Res  2009; 154: 183– 193. Google Scholar CrossRef Search ADS PubMed  128. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol  2013; 304: H1598– H1614. Google Scholar CrossRef Search ADS PubMed  129. Nishimura N, Schaffer CB, Friedman B, Lyden PD, Kleinfeld D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci USA  2007; 104: 365– 370. Google Scholar CrossRef Search ADS PubMed  130. Tagami M, Nara Y, Kubota A, Fujino H, Yamori Y. Ultrastructural changes in cerebral pericytes and astrocytes of stroke-prone spontaneously hypertensive rats. Stroke  1990; 21: 1064– 1071. Google Scholar CrossRef Search ADS PubMed  131. Dore-Duffy P, LaManna JC. Physiologic angiodynamics in the brain. Antioxid Redox Signal  2007; 9: 1363– 1371. Google Scholar CrossRef Search ADS PubMed  132. Faraco G, Park L, Anrather J, Iadecola C. Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med (Berl)  2017; 95: 1143– 1152. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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American Journal of HypertensionOxford University Press

Published: May 17, 2018

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