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Ageing and microvasculature

Ageing and microvasculature A decline in the function of the microvasculature occurs with ageing. An impairment of endothelial properties represents a main aspect of age-related microvascular alterations. Endothelial dysfunction manifests itself through a reduced angiogenic capacity, an aberrant expression of adhesion molecules and an impaired vasodilatory function. Increased expression of adhesion molecules amplifies the interaction with circulating factors and inflammatory cells. The latter occurs in both conduit arteries and resistance arterioles. Age-related impaired function also associates with phenotypic alterations of microvascular cells, such as endothelial cells, smooth muscle cells and pericytes. Age-related morphological changes are in most of cases organ-specific and include microvascular wall thickening and collagen deposition that affect the basement membrane, with the consequent perivascular fibrosis. Data from experimental models indicate that decreased nitric oxide (NO) bioavailability, caused by impaired eNOS activity and NO inactivation, is one of the causes responsible for age-related microvascular endothelial dysfunction. Consequently, vasodilatory responses decline with age in coronary, skeletal, cerebral and vascular beds. Several therapeutic attempts have been suggested to improve microvascular function in age-related end-organ failure, and include the classic anti-atherosclerotic and anti-ischemic treatments, and also new innovative strategies. Change of life style, antioxidant regimens and anti-inflammatory treatments gave the most promising results. Research efforts should persist to fully elucidate the biomolecular basis of age-related microvascular dysfunction in order to better support new therapeutic strategies aimed to improve quality of life and to reduce morbidity and mortality among the elderly patients. Keywords: Endothelial cells, Smooth muscle cells, Endothelial dysfunction, Nitric oxide, Vascular remodelling, Organ-specific ageing Introduction transvascular exchange and fluid economy [8]. Therefore, Vascular ageing is associated with both structural and cell survival depends on adequate microvascular perfusion functional changes that can take place at the level of [8]. The architecture and the biophysical behavior of the endothelium, vascular smooth muscle cells and the flowing blood strongly influence microvascular function. extracellular matrix of blood vessels [1]. Age, hypertension, Morphologically, the microcirculation is constituted from diabetes, smoking and plasma low density lipoprotein vessels <300 μm in diameter [8]. Therefore, it includes cholesterol level are determinant risks of arterial stiffness arterioles, capillaries, and venules (Figure 1). Alternatively, [2,3]. A relevant age-related vascular change is a progressive a physiological definition based on vessel function rather myointimal thickening [4,5]. Similarly to that observed than diameter or structure has been proposed [9]. By this in large vessels, age-related increase of microvascular tone definition, vessels that respond to an increase of pressure leads to a progressive myogenic hypertrophic remodelling by a myogenic reduction in lumen diameter are consid- of small arteries, due to the increased distending pressure ered part of the microcirculation [9]. Consequently, be- acting perpendicularly on the vascular wall [6]. Micro- sides endothelial cells, also vascular smooth muscle cells vascular alterations play an important role in ageing- (VSMCs) and pericytes must be included in the micro- associated end-organ damage [7]. In fact, microcirculation vascular cell population. Although the primary function is provides the interface for tissue delivery of oxygen and to optimise the nutrient and oxygen supply, microcircula- nutrients, removal of waste products and carbon dioxide, tion is relevant in order to avoid large hydrostatic pressure fluctuations causing disturbances in capillary exchange and an overall peripheral vascular resistance [10]. An im- * Correspondence: [email protected] portant role in regulating tissue fluid balance and in Department of Biomedicine and Prevention, Institute of Anatomic Pathology, Tor Vergata University, Via Montpellier, Rome 00133, Italy © 2014 Scioli et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Scioli et al. Vascular Cell 2014, 6:19 Page 2 of 15 http://www.vascularcell.com/content/6/1/19 Figure 1 Schematic representation of microcirculation components. The microcirculation is a network of small blood vessels, including arterioles, venules and capillaries. Blood flows from the arteries into the arterioles and then pass into the venules across true capillaries or throughfare channels and metarterioles (arteriovenous bypass). The precapillary sphincter, made of smooth muscle cells, controls blood flow into the true capillaries. As blood travels through the capillaries, plasma proteins and fluid enter the interstitial space according to hydrostatic and osmotic pressure gradients. Most of the fluid is reabsorbed into the post-capillary venules, while a fraction enters to the lymphatic circulation for its return to the blood circulation. maintaining osmotic and hydrostatic pressures is played main component of ROS is the superoxide anion (O2-), by the lymphatic system (Figure 1), that comprises a one- which for its high cytotoxic activity is transformed quickly way transport for fluid and proteins by collecting them into hydrogen peroxide (H2O2) by superoxide dismutase from the interstitial space and returning them to the blood (SOD). The H2O2 is transformed in H2O by two enzymes, circulation [11]. This review focuses the attention on the catalase and glutathione peroxidase (GPx) [16]. biomolecular and pathophysiological mechanisms under- As reported, with ageing H2O2 production is enhanced lying age-related microvascular alterations and the [17], leading to the increase of mitochondrial H2O2 and importance of new therapies to prevent end-organ O2- generation, cumulative DNA damage and cellular damage associated with microvascular dysfunction. senescence [18-20]. Moreover, mitochondria are not only targets for ROS but also significant sources of ROS, Biomolecular mechanisms involved in age-related which under certain conditions may stimulate NAD(P)H microvascular dysfunction oxidases [12]. In fact, many studies demonstrated the Reactive oxygen species and oxidative stress principal role of NAD(P)H oxidase activity in aged- The primary mechanism involved in ageing-associated mediated ROS generation in mouse models [21-23] and microvascular dysfunction is the oxidative stress, a state in the improvement of endothelial function by the inhib- which the generation of reactive oxygen species (ROS) ition of NAD(P)H oxidase or scavenging of O2- [24,25]. exceeds the antioxidant defense systems, resulting in In particular, it has been reported that NAD(P)H oxidase cellular dysfunction and apoptosis [12]. Physiologically, 4 is involved in O2- formation and cellular senescence ROS are involved both in the maintenance of steady in ageing, and its inhibition counteracted oxidative vessel wall conditions and in the vascular response to stress in pulmonary and kidney arteries of aged rats, as altered flow or pressure settings [12]. Vascular cells com- well as in lungs of aged mice [26-28]. prise different sources of ROS, including enzymatic activity of NAD(P)H oxidase, xanthine oxidase (XO), uncoupled Nitric oxide endothelial nitric oxide (NO) synthase (eNOS), cytochrome In mammals, nitric oxide (NO) is produced by a family P450 and the mitochondrial respiratory chain [13-15]. The of enzymes, named nitric oxide synthases (NOSs), that Scioli et al. Vascular Cell 2014, 6:19 Page 3 of 15 http://www.vascularcell.com/content/6/1/19 catalyse the production NO from L-arginine. NO is an overexpression caused vascular senescence by mitochon- important cellular signalling molecule that regulates vaso- drial and NADPH-dependent superoxide generation [18]. dilatation, insulin secretion, airway tone, and peristalsis, This mechanism was attenuated by mitochondrial electron and is involved in angiogenesis and neural development transport chain or angiotensin type 1 receptor inhibitors [29]. The family of enzymes NOS comprises three iso- [39,40]. Moreover, the infusion in rats of angiotensin II forms: neuronal NOS (nNOS/NOS1), inducible NOS induced microvascular lesions in various vascular beds that (iNOS/NOS2) and endothelial NOS (eNOS/NOS3) [29] resemble arteriolosclerosis [41]. The blocking of nitric oxide eNOS constitutively produces NO in endothelial cells and synthesis also induced renal microvascular disease [42]. physiologically contributes to the control of vascular tone. It is well known that angiogenesis and wound healing Instead iNOS is activated by bacterial lipopolysaccharide, are reduced with ageing [43]. In fact, vascular endothelial cytokines, and other inflammatory agents, determining an growth factor (VEGF)-induced angiogenesis is attenuated abnormal production of NO. Due to its affinity to protein- in aged rats and rabbits [44,45]. In aged mice and in cul- bound iron, NO can inhibit key enzymes that contain tured human microvascular endothelial cells aged by iron in their catalytic centers. These include iron–sulfur progressive passaging, the expression of the tissue inhibi- cluster-dependent enzymes (complexes I and II) involved tor of metalloproteinase-2 (TIMP-2) is increased [46], and in mitochondrial electron transport, ribonucleotide reduc- correlated with an attenuated capacity of endothelial cells tase (the rate-limiting enzyme in DNA replication), and to degrade extracellular matrix, a process required for cis-aconitase (a key enzyme in the citric acid cycle) [29]. angiogenesis [46]. As discussed above, microvascular dysfunction is mainly Taken together these findings suggest the existence of a induced by the over-production and release of O2-, which complex biomolecular mechanism involved in age-related cause NO breakdown. In fact, NO inactivation is due to vascular dysfunction that leads to oxidative stress, vascular its reaction with O2- to form the potent oxidant peroxyni- remodelling and endothelial dysfunction. This altered sig- trite (ONOO ) [30]. This compound can cause oxidative nalling, in endothelial cells, causes the activation of NF-kB damage, nitration, and S-nitrosylation of biomolecules in- and a consequent abnormal gene transcription, including cluding proteins, lipids, and DNA single-strand breakage the enhancement of cellular adhesion molecule expres- following the poly-ADP-ribose polymerase (PARP) activa- sion, such as intercellular adhesion molecule-1 (ICAM-1), tion [31-33]. The increase of nitration was demonstrated vascular cell adhesion molecule-1 (VCAM-1), E-selectin, in the sarcoplasmic reticular Ca-ATPase isolated from the and inflammatory cytokine secretion [47-49]. This process skeletal muscle of old rats [34]. The scavenging of NO by determines the leukocyte recruitment and extravasation as O2- was also demonstrated in coronary microvascular also demonstrated in the vascular wall of aged rabbits [50]. endothelial cells of old rats, in which the reduction of A schematic representation of age-related biomolecular eNOS expression was accompanied with an increased alterations in microcirculation is reported in Figure 2. O2- production and attenuated vasodilator responses [35]. Coronary arterioles of aged rats displayed an increased Structural and functional microvascular alterations iNOS activity and ONOO production, as well as a de- involved in ageing creased eNOS expression [36]. The same alterations have Arteriolosclerosis been also described in elderly [36]. Microvascular disease is also referred as an impairment of Moreover, oxidative stress can convert eNOS from a flow-induced dilatation of arterioles, defined arteriolo- NO-producing enzyme to an enzyme that generates O2-. sclerosis [51]. Arteriolosclerosis is due to stiffening, with This process is named eNOS uncoupling. Mechanisms loss of elasticity, of arterioles and must be distinguished implicated in eNOS uncoupling include oxidation of the from arteriosclerosis, a hardening with loss of elasticity critical NOS cofactor BH , depletion of L-arginine, and of medium or large arteries, and from atherosclerosis, a accumulation of endogenous methylarginines [29]. stiffening of an artery specifically due to an atheromatous plaque. Arteriolosclerosis is characterised by intimal thick- Age-related signal alterations in vascular cells ening, vascular smooth muscle cell proliferation, and It has been demonstrated that endothelin-1 and angioten- extracellular matrix deposition, resulting in an increased sin II (potent vasoconstrictors) pathways are involved in media-to-lumen ratio, and later by the replacement of the age-related endothelial oxidative stress [18]. In particular, vascular smooth muscle cells by areas of fibrosis and ageing induced endothelin-1 overexpression, resulting in cell loss [51]. Consequently, arteriolosclerosis may have vascular remodelling and endothelial dysfunction in mice a key role in mediating the development of chronic kidney [37]. In addition, it has been reported the involvement disease, vascular dementia, stroke and coronary heart dis- of endothelin-1 in eNOS downregulation in pulmonary ease [51]. Hyaline arteriolosclerosis refers to a thickening artery endothelial cells of fetal porcine [38]. As concerning of the wall of arterioles by the deposition of homogeneous angiotensin II, it has been documented that in ageing its pink hyaline material and can involve multiple organs, Scioli et al. Vascular Cell 2014, 6:19 Page 4 of 15 http://www.vascularcell.com/content/6/1/19 Figure 2 Schematic representation of biomolecular changes in age-related microvascular dysfunction. Oxidative stress plays a pivotal role in endothelial and myocitic impaired function. including brain (Figure 3). Structural and functional alter- and exhibits an increased uptake of modified low-density ations described above involve all microvascular compo- lipoprotein (LDL) and decreased NO production [58]. For nents, including endothelial cells, pericytes and smooth example, as documented in aged rats, important structural muscle cells. Below are summarised the principal features changes of brain capillaries were found: thickening of the of age-related microvascular cell changes. basal lamina and the thinning of endothelial cells [59]. Some suggestthatthis phenomenonis due to aloss Endothelial cells of endothelial cells together with a lengthening of As a consequence of the alteration in the expression and/ the remaining ones to allow nutrients to diffuse [60]. or activity of eNOS, upregulation of iNOS, and increased Mophological alteration of aged endothelium was observed formation of ROS and ONOO , endothelial cells undergo also in sinusoids of human aged liver, where thickening to cumulative DNA damage that promotes senescence of the sinusoidal endothelium was associated with the and apoptosis [52]. As described above, the age-related deposition of basal lamina and collagen [61]. In the kidney decline of endothelial function becomes manifest through of aged rats the number of proliferating endothelial cells a reduced regenerative and angiogenic capacity, and an was decreased compared with young rats. In addition, altered expression of adhesion molecules regulating the VEGF expression strongly decreased with ageing in the interaction of circulating factors with immune system endothelium of the outer and inner medulla, suggesting a cells [53,54]. reduced angiogenic activity [62]. The attenuated capacity of the endothelium to regen- erate is partially a consequence of an impaired secretion Smooth muscle cells and pericytes of and/or sensitivity to growth factors [55]. Recently, the As discussed above, in ageing, upregulation of pro-oxidants regeneration of the endothelium by bone marrow-derived and downregulation of antioxidants results in an imbalance circulating progenitor cells has gained particular attention, leading to ROS increase [63-65] and to the development of because the number of circulating endothelial progenitor vascular dysfunction in both animal models and in humans cells (EPCs) decreases with age and is thought to reflect the [66]. In old rats, a significant increase in O2- was observed attenuated mobilization of these cells from the bone mar- in the vascular wall [67], and was associated with an row [56]. Moreover, EPCs from older subjects have a re- increase in NAD(P)H oxidase activity [36,64,68-70]. It has duced capacity to engraft [57]. Some studies suggest that been also reported that Angiotensin II pathway plays an the regenerated endothelium is functionally impaired [57] important role in age-related smooth muscle cell oxidative Scioli et al. Vascular Cell 2014, 6:19 Page 5 of 15 http://www.vascularcell.com/content/6/1/19 Figure 3 Age-related changes of brain microvasculature. Post-mortem (myocardial acute infarction) histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed cerebral tissue. PAS staining of human brain gray matter, showing normal capillaries and arterioles in a young (A,C) compared to concentrically thickened microvessels in an aged man (B,D) mostly due to hyalinization (pink staining). Masson's trichrome staining shows normal microvessel in a young (E) and perivascular deposition of collagen (blue staining) around capillaries in an aged man (F). Immunohistochimical analysis for α-SMA shows normal arteriole in a young (G) and concentrically thickened arteriole due to an altered proliferation of smooth muscle cells in an aged man (H). Magnification 40×. stress by eliciting NAD(P)H oxidase activity [71]. In fact, can also induce the activityofiNOSthrough theNF-kB Angiotensin II stimulation induced the NAD(P)H oxidase- pathway under inflammatory conditions [64], as also dependent O2- production, stimulating NF-κB signalling reported in aged Macaca mulatta, rats [64,74] and mice in senescent VSMCs [72]. Similarly to endothelial cells, [75]. As already reported, vascular ageing is also associated VSMCs of old rats in response to cytokines showed higher with a progressively reduced NO bioavailability. Since ICAM-1 level compared with newborn rats [73]. VSMCs VSMCs are important targets for endothelium-derived Scioli et al. Vascular Cell 2014, 6:19 Page 6 of 15 http://www.vascularcell.com/content/6/1/19 NO, this reduction causes an impairment of endothelium- Lymphatic vessel alterations dependent vasodilation [76]. In addition, the in vitro Lymphatic system begins when the plasma fluid and response of VSMCs to NO and β-adrenoreceptor stimula- proteins, that are forced out by arterial capillaries into tion is decreased by ageing, and such changes may the interstitial space (Figure 1), are collected into the contribute to impairment of endothelium-independent lymphatic capillaries, which are freely permeable to vasodilation in the elderly [76,77]. Consequently to macromolecules [90]. So, the main function of lymphatic age-related oxidative stress and impaired signalling trans- system is to maintain osmotic and hydrostatic pressures duction, VSMCs undergo to phenotypic alteration, prolifer- within the tissue space. It consists of capillaries (10-60 μm ation, migration, dedifferentiation and extracellular matrix in diameter) that drain lymph into the collecting vessels remodelling, as reported in coronary resistance arterioles that contain also smooth muscle. The fluid pass through of old rats [5]. The series of events lead to increased vessel several clusters of lymph nodes and then into larger wall thickness, inflammation, and vulnerability to the de- trunks, which in turn lead into the ducts, that return velopment of vascular dysfunction [64,78]. VSMCs lose lymph back into the bloodstream [11]. their specialised or differentiated properties and become Spontaneous contractions of smooth muscle cells in proliferative and highly motile [5,79]. Extracellular matrix the wall of lymphatic vessels are necessary to maintain reorganization occurs with ageing, such as collagen increase effective lymph flow whereas proper functioning of lymph- and elastin fragmentation [80]. These changes in the atic endothelial cells is necessary to regulate lymphatic relative content and organisation of collagen and elastin contractility [91]. The basic self-regulatory mechanisms result in increased fibrosis and contribute to the stiffening controlling lymph flow in lymphatic vessels is realised of the vascular wall [81]. It may be due to alternative through the sensitivity of their muscle cells to levels of signal transduction pathways revealed by the ability of the stretch and of their endothelial cells to levels of the shear older cells to respond to inhibitors, such as transforming stress [91]. Nitric oxide plays an important functional role growth factor-β1, or to altered interactions with the extra- in coordinating the lymphatic contractile cycle [92] and in cellular matrix resulting from age-associated shifts in fine tuning lymphatic contractions to different levels of integrin expression [54]. Both b1 integrin, adhesive basal luminal flow [93]. Zhdanov and Zerbino reported interactions with fibronectin and α-smooth muscle actin ageing-related changes in morphology of various human (α-SMA) are also major players in VSMC stiffening [82]. lymphatic networks in the early 1960s [90,94,95]. They Pericytes, the mural cells on capillaries, play an important observed a reduction in the number of lymphatic capil- role in vessel stabilisation, by regulating endothelial cell laries (nonmuscular initial lymphatics) through all of the proliferation and preventing capillary withdrawal [83-85]. body and the presence of specific “varicose bulges,” which Alterations in these cells with ageing also might contribute exist in muscular lymphatic vessels. It has also been to the development of age-related morphological and reported that aged thoracic duct showed signs of lipid physiological abnormalities of the microvasculature. In accumulation, thickening, and fibrosis [90,96]. fact, microvascular ageing is characterised by changes Recently, some authors reported changes in orientation in peripheral capillaries, including vessel broadening, and investiture of muscle cells in mesenteric lymphatic and thickening of the basement membrane, as well as vessels in aged rats [90,91]. It has been postulated that altered length and orientation of desmin filaments in in elderly the decrease of accessory muscle elements pericytes [86]. These changes can determine a reduced surrounding lymphatic valve may limit the ability of pericyte–endothelial cell contact, destabilisating capillaries lymphatic vessels to adapt their contractility to various [86]. In addition, a reduction in pericyte number in aged preload/afterload challenges with subsequent formation capillaries was also reported [87]. In the brain capillaries of lymph stasis and potential spread of pathogens and of elderly the decrease in pericyte coverage was reported immune cells in direction opposite to the direction of [88]. It has been also documented that in the retina of the normal lymph flow [90]. In addition, the thin-walled old rats, ageing induced the broadening of peripheral low muscle cells investiture zones in aged rats may be capillaries and terminal venules, as well as thickening transformed to aneurysm-like formations “varicose bulges”, of basement membranes [86]. In the retina of old rats which can be ideal places for formation of low-velocity was reported a shift from a pericyte phenotype toward turbulent lymph flow and accumulation of various mol- an arteriolar smooth muscle cell–like phenotype. It was ecules, pathogens, and cancer cells [90]. Some studies associated with an increase in calponin labelling of reported a reduced lymph flow in aged animals in vivo arterioles, thickness of basement membranes, and increased [97,98]. Ageing severely altered contractility of the toracic focal adhesions in arteriolar walls [86]. Moreover, in skeletal duct through weakening of lymphatic contractions and muscle of old mice, the muscular regenerative capacity complete depletion of their shear/nitric oxide (NO)- of pericytes is limited, and they produce collagen and dependent regulation [98]. It has been demonstrated contribute to fibrous tissue depositing [89]. that ageing severely altered NO-dependent regulation of Scioli et al. Vascular Cell 2014, 6:19 Page 7 of 15 http://www.vascularcell.com/content/6/1/19 thoracic duct contractions with an impaired eNOS function to overexpression of the transcription factors: serum and an ageing-associated shear-independent NO release in response factor (SRF) and myocardin [105]. In the duct due to iNOS activation [98]. Non-specific nitric addition, SRF and myocardin may also regulate con- oxide synthase (NOS) blockade restored the contraction tractile proteins in VSMCs, thus altering normal vessel [98]. These findings provided functional consequences of physiology [106]. ageing in lymphatic contractility and the dysfunctional responses of smooth muscle cells and endothelium in Liver ageing-induced alterations [98]. Age-related changes in the human hepatic sinusoidal endothelium, termed pseudocapillarisation, have been recently described and they contribute to the impairment Age-related changes of end-organ microvasculature of hepatic function [107]. Blood clearance of a variety As a consequence of the age-related alterations in the of waste macromolecules takes place in liver sinusoidal expression and/or activity of eNOS, upregulation of iNOS, endothelial cells (SECs) [108]. These cells are unique increased formation of ROS and ONOO-, and extracellular endothelial cells in both their architecture and their matrix remodelling, vasodilatory function is impaired and function. The sinusoids are the exchange vessels of the an excessive capillary pressure with consequent hyperfiltra- liver, and the SECs are distinguished by extensive fenes- tion, protein leakage, edema formation and tissue damage trations organized into sieve plates, a lack of a basement occur. In small arteries and arterioles, which have a relative membrane, and low junctional expression of CD31 [108]. higher wall thickness, changes in tone and circumferential The SEC architecture, including open fenestrations and shortening have an enhanced effect on lumen diameter, weak junctional association between cells, provides a resulting in a blood flow decline in many organs [7]. We dynamic filtration system with low perfusion pressure describe the main alterations that characterise the age- that enables nutrients and macromolecular waste to related end-organ damage. pass freely to hepatocytes for efficient metabolism [108]. The maintenance of SEC phenotype is a critical Brain process that requires both autocrine and paracrine cell Cognitive dysfunction from lower perfusion and micro- signalling [108]. Recent studies indicate that fenestra- vascular fibrohyalinosis is the most common type of tions are maintained by constitutive VEGF-stimulated microvascular damage in the elderly [99]. Atherosclerosis NO generation in SECs and surrounding cells [109]. In in elderly people also coincides with massive microvascular response to ageing [110], SECs dedifferentiate into a more fibrosis, which contributes to the development of white regular endothelium, hence the term capillarisation or matter lesions, myelin rarefaction or demyelination, gliosis, pseudocapillarisation. The hallmarks of capillarisation apoptosis and regressive astrocytic changes [99-101]. Thick- are SEC defenestration, development of a laminin-rich ening of small vessels was associated with diffuse white basement membrane, junctional expression of CD31 matter lesions in elderly [102]. Reduced pericyte–endothe- and protein nitration, in a mechanism involving NAD(P)H lial cell contact also occurs [86]. oxidase–generated ROS [108]. In addition, sinusoidal Brain arteriolosclerosis is a subtype of cerebrovascular stellate cells are also induced to overexpress a laminin and pathology characterised by concentrically thickened arte- collagen matrix that contributes to fibrosis [111]. rioles due to an altered proliferation of smooth muscle In autoptic studies of older human subjects, independ- cells and excessive extracellular matrix deposition [103], ently from the presence of systemic diseases or hepatic as also shown in our histological study (Figure 3). pathologies, pseudocapillarisation occurs from increased Cerebral amyloid angiopathy (CAA) is another micro- peri-sinusoidal expression of von Willebrand’sfactor, vascular pathology associated with ageing and results from CD31 and collagen I and IV, resulting in a thickening and deposition of β-amyloid in the media and adventitia of defenestration of the liver sinusoidal endothelium and small arteries and capillaries of the leptomeninges and deposition of basal lamina in the extracellular space of cerebral cortex and is a major cause of lobar intracerebral Disse [61,107], as also shown in our histological study hemorrhage and cognitive impairment in the elderly [104]. (Figure 4). In addition, it has been reported an endothelial CAA is present in nearly all brains with Alzheimer disease, upregulation of ICAM-1 [61]. Transmission electron mi- suggesting a common β-amyloid-based pathogenesis for croscopy study revealed a significant age-related thickening these diseases. However, despite the close molecular of the sinusoidal endothelium, with loss of fenestrations relationship between the two diseases, CAA remains a [61]. Loss of fenestrations leads to impaired transfer of clinically distinct entity from Alzheimer disease [104]. lipoproteins from blood to hepatocytes. This provides a The accelerated β-amyloid vascular deposition in mechanism for impaired chylomicron remnant clearance CAA seems to be caused by a transcriptional deregu- and postprandial hyperlipidemia associated with old lation of the lipoprotein receptor LRP in VSMCs due age [112]. Scioli et al. Vascular Cell 2014, 6:19 Page 8 of 15 http://www.vascularcell.com/content/6/1/19 Figure 4 Microscopic aspects of human liver pseudocapillarisation. Post-mortem (myocardial acute infarction) histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed liver tissue. Masson's trichrome staining shows the central vein and pericentral hepatocytes of young (A) and old liver (B) with perisinusoidal collagen deposition (blue staining). CD31 immunostaining of young (C) and old liver (D) with an increased sinusoidal protein expression. Magnification 20×. Heart and platelets [119]. Taken together, these findings suggest Ageing is also associated with functional changes of that arteriolar changes, induced by ageing-related oxidative the coronary microvasculature [113]. An important stress, impairs the vasoactive function of the coronary mechanism that contribute to the local regulation of vessels in ageing. myocardial blood flow is the flow (shear stress)–induced NO mediated dilatation of small coronary arteries and ar- Kidney and skin terioles [114]; so ageing, that impairs NO synthesis/release With ageing, a degenerative process occurs with the in the endothelium (as described above), determines a appearance of glomerular lesions, as a thickening of the vasodilatory dysfunction also in rat coronary arterioles glomerular basement membrane and Bowman’s capsule [115]. It was also reported an increased breakdown of NO [120], parallel to glomerulosclerosis, interstitial fibrosis due to an augmented arteriolar production of O2- [116]. and progressive proteinuria [121]. Biochemical studies Moreover, in isolated coronary arterioles of old rats, evidenced the age-related increase of collagen and decrease with an impaired flow-induced dilatation, O2- and in glycosaminoglycans, particularly of heparan sulphate ONOO- production increased both in endothelial and [122]. Ultrastructural studies, conducted in our laboratory, VSMCs [36]. In addition, eNOS and SOD activity were documented a marked thickening of the glomerular base- impaired, whereas NAD(P)H oxidase and iNOS were up- ment membrane in old rats (Figure 5A-B). In addition, regulated. [36]. Aged human and rabbit small coronary young rats perfused with cationized ferritin in vivo showed vessels show a marked increase of myocardial interstitial a regular distribution of these molecules, along the in- collagen, with α-SMA and TGFβ-1 negative fibroblasts ternal and external lamina rara of the glomerular base- and VCAM-1 positive microvessels without macrophages ment membrane (Figure 5C). In the old rats, ferritin was [117,118]; these findings support the close link between present only along the internal lamina rara (Figure 5D), endothelial dysfunction and age-related fibrosis [117,118]. suggesting that the age-related loss of anionic charged of The impaired coronary endothelial function may result in heparan sulphate molecules is responsible for age-related adverse clinical events because of the increased vascular proteinuria, also reported in human. In the kidney of aged and perivascular recruitment of neutrophils, macrophages, rats, the glomerular and peritubular capillary loss Scioli et al. Vascular Cell 2014, 6:19 Page 9 of 15 http://www.vascularcell.com/content/6/1/19 Figure 5 Ultrastructural aspects of age-related changes in rat kidney microvessels. Glomerular basement membrane of kidney in young (A) and old rat (B), that shows the characteristic thickening of capillary wall. Magnification 5000×. Cationized ferritin distribution on glomerular basement membrane of young (C) and old rat kidney (D). Magnification 30000×. correlates with alterations in VEGF and TSP-1 expression decrease in eNOS expression in peritubular capillaries and also with the development of glomerulosclerosis and [127]. In addition, it has been reported that ageing induced tubulointerstitial fibrosis, suggesting an impaired angio- oxidative stress in kidney and the attenuation of redox genesis associated with progressive loss in renal microvas- status can ameliorate microvascular function [128]. Renal culature [62]. The mechanism of capillary loss in oxidative stress was associated with an increase in aged kidney has not been fully understood. Angiosta- ONOO , NO and ROS levels, as well as iNOS activity tin is a potent inhibitor of angiogenesis in vivo. In [129]. Treatment with an antioxidant reduced the age- aged rats angiostatin production is increased, as well related renal dysfunction [129]. Moreover, in aged rats, as the activity of cathepsin D, the enzyme for angios- NF-κB activation has been reported to contribute to the tatin production [123]. In addition, NO availability is accumulation of oxidative stress [130]. decreased and cathepsin D activated, suggesting a pos- Structural and functional alterations of the skin during sible correlation between the increase of angiostatin the ageing process are due to some complex mechanisms, production, capillary loss and interstitial damage in determined by intrinsic and extrinsic factors, which act aged rat kidney [123]. NOS inhibition by L-NAME pro- synergistically [131]. Collagen fibers become thinner and duced a stronger vasoconstriction in renal vessels of change their aspect; in the deep dermis they become more old compared with young rats [124,125], suggesting fibrous. Thickened microvessels can be recognised by the that endogenous NO production is necessary for the increased intensity of the vascular PAS positive-diastase control of renal circulation. Moreover, post-mortem an- resistant staining, and by the perivascular collagen depos- giograms and histology studies, in elderly, showed wall ition (Figure 6). Elastic fibers show the tendency of frag- thickening and narrowing of the vascular lumen of af- mentation, with a pathological assembly [131,132]. With ferent arterioles, an alteration mainly depending on ageing, a progressive reduction of dermis vasculature is VSMC proliferation [126]. present, due to a reduction in the number and size of Tubulointerstitial fibrosis, in aged rats, was characterised vascular vessels [131]. Age-related decrease in the number by tubular injury and focal tubular cell proliferation, myofi- of dermal blood vessels is suggested to be due to an broblast activation, macrophage infiltration with increased impairment of VEGF signalling [133]. In addition, it has immunostaining for the adhesive proteins osteopontin been reported that eNOS activity is required for full and ICAM-1, and collagen IV deposition, as well as a expression of reflex cutaneous vasodilation, and its Scioli et al. Vascular Cell 2014, 6:19 Page 10 of 15 http://www.vascularcell.com/content/6/1/19 Figure 6 Ageing in skin microcirculation. Histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed skin of healthy subjects. Masson's trichrome staining shows collagen distribution (blue staining), around microvessels, in young (A) and old dermal skin (B). PAS staining shows hyaline deposits (pink staining), around microvessels, in young (C) and old dermal skin (D). CD31 immunostaining of young (E) and old dermal skin (F) showing the descrease of capillaries associated with ageing process. α-SMA immunostaining of young (G) and old dermal skin (H) showing the proliferation of VSMCs around aged microvessels. Magnification 40×. Scioli et al. Vascular Cell 2014, 6:19 Page 11 of 15 http://www.vascularcell.com/content/6/1/19 impairment in aged skin is associated with alterations Ascorbate is essential for normal endothelial function in NO signalling [134], increase of oxidative stress and [155] and prevents microvascular dysfunction and H2O2- upregulation of arginase [135]. mediated injury in cultured microvascular endothelial cells [144]. Other natural substances, such as aged garlic extract and resveratrol, have been documented to minimise oxida- Therapeutic targeting of microvascular ageing tive stress and to stimulate endothelial NO generation, Being assumed that microvascular dysfunction plays a key suggesting that antioxidant regimens can be efficacy to role in age-related end-organ failure, several therapeutic counteract adverse clinical effects of age-related micro- attempts have been suggested. We summarised the most vascular endothelial dysfunction [74,75,156]. In vitro studies diffuse anti-atherosclerotic and anti-ischemic treatments suggest that the molecular mechanisms of resveratrol- and more anti-ageing innovative strategies. mediated vasoprotection involve NF-kB inhibition, upreg- ulation of eNOS and antioxidant enzyme levels, and the Changes of lifestyle, anti-atherosclerotic and anti-ischemic prevention of oxidative stress–induced apoptosis [157,158]. treatments Resveratrol supplementation may confer a significant vaso- Due to a high burden of cardiac risk factors and coronary protection in elderly humans [63]. atherosclerosis in subjects with angina and no obstructive coronary artery disease, lifestyle changes to modify risk factors are fundamental [136,137]. Cardiac rehabilitation Novel anti-inflammatory therapies is recommended for those patients who have limited Vascular ageing is associated with deregulation of TNF-α physical activity; increased exercise capacity is related to expression [36,159]. TNF-α is a master regulator of vascular the amelioration of atherosclerotic disease symptoms [138]. inflammatory cytokines, chemokines and adhesion mole- Statins may improve endothelial function by lipid- cules. TNF-α plasma level increases with ageing and corre- independent anti-inflammatory and antioxidant properties lates with morbidity and mortality in the elderly patients and the capacity to restore microvascular NO availability [160,161]. Consequently an anti-TNF-α treatment (i.e., with [139]. Angiotensin-converting enzyme inhibitors as well as etanercept, which binds and inactivates TNF-α) may exert angiotensin-renin blockers [140] have been shown to im- vasoprotective effects, including a reduction of endothelial prove endothelium-dependent relaxation of coronary arter- cell apoptosis and the downregulation of NAD(P)H oxi- ies by increasing NO availability [141]. Upregulation dases activity [162]. Pharmacological inhibition of the poly of arginase has emerged as an important factor con- (ADP-ribose) polymerase (PARP) pathway also represents tributing to reduce NO production by competing with a novel therapeutic target to improve ageing-associated endothelial NO synthase for the common precursor cardiovascular dysfunction [163]. substrate L-arginine [142]. Arginase inhibitors may in- duce long-term improvement of microvascular func- tion and limitation of myocardial injury following Conclusions ischaemia–reperfusion [143]. Ageing elicits several structural and functional changes in the microvasculature. Reactive oxygen species and Antioxidant therapy the concomitant oxidative and nitrosative stress play an Some works focused the attention on antioxidant agents important role in the process of ageing-related micro- that can prevent or reduce the progression of end-organ vascular dysfunction, affecting vascular function as well microvascular dysfunction [144]. Antioxidants and free as signalling transduction and gene expression. Although radical scavengers such as N-acetyl-cysteine (NAC), a significant progress has been achieved in describing the ascorbic acid and Propionyl-L-carnitine (PLC) showed a intrinsic age-related alterations of microvascular function, clinical efficacy in patients with endothelial dysfunction the age-related decline in endogenous antioxidant mecha- [145-149]. NAC, a derivative of cysteine, and ascorbic nisms, angiogenesis, endothelium-dependent vasodilation acid induced beneficial effects on oxidative stress and vas- and microvascular permeability remains to be fully cular dysfunction [145-147]. PLC is an ester of L- assessed. Increased knowledge may lead to new therapies carnitine, that is required for the transport of fatty acids targeting microvascular dysfunction and to improve clinical into the mitochondria [150]. PLC has been reported to outcome. A key observation is that new therapeutic oppor- modulate NF-kB activity in vascular cells [151] and to re- tunities aimed to favour microvascular function are also duce age-related microvascular dysfunction and myocar- associated with ameliorated organ function. An appropri- dial remodelling, including adhesion molecule expression ate control of ageing process, in particular of oxidative [152]. In addition, it has been reported that PLC coun- stress, can clarify the efficacy of many pharmacological or teracts membrane lipid peroxidation and reduces post- nutritional approaches in order to delay the onset of age- ischemic endothelial dysfunction [153,154]. dependent microvascular disease. Scioli et al. Vascular Cell 2014, 6:19 Page 12 of 15 http://www.vascularcell.com/content/6/1/19 Competing interests 21. Geng L, Cahill-Smith S, Li JM: 190 Nox2 activation and oxidative damage The authors declare that they have no competing interests of cerebral vasculature and locomotor function in ageing mice. Heart 2014, 100(Suppl 3):A105–A106. 22. Paneni F, Osto E, Costantino S, Mateescu B, Briand S, Coppolino G, Perna E, Authors’ contributions Mocharla P, Akhmedov A, Kubant R, Rohrer L, Malinski T, Camici GG, Matter MGS, AB, GA: writing of the manuscript; AF: revision of the manuscript; CM, Mechta-Grigoriou F, Volpe M, Lüscher TF, Cosentino F: Deletion of the AO: financial support, administrative support, writing and final approval of activated protein-1 transcription factor JunD induces oxidative stress the manuscript. All authors read and approved the final manuscript. and accelerates age-related endothelial dysfunction. Circulation 2013, 127:1229–1240. Acknowledgments 23. 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Li P, Park C, Micheletti R, Li B, Cheng W, Sonnenblick EH, Anversa P, Bianchi G: • Research which is freely available for redistribution Myocyte performance during evolution of myocardial infarction in rats: effects of propionyl-L-carnitine. Am J Physiol 1995, 268:H1702–H1713. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Vascular Cell Springer Journals

Ageing and microvasculature

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Medicine & Public Health; Angiology; Cardiology; Cancer Research; Cell Biology; Developmental Biology
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Abstract

A decline in the function of the microvasculature occurs with ageing. An impairment of endothelial properties represents a main aspect of age-related microvascular alterations. Endothelial dysfunction manifests itself through a reduced angiogenic capacity, an aberrant expression of adhesion molecules and an impaired vasodilatory function. Increased expression of adhesion molecules amplifies the interaction with circulating factors and inflammatory cells. The latter occurs in both conduit arteries and resistance arterioles. Age-related impaired function also associates with phenotypic alterations of microvascular cells, such as endothelial cells, smooth muscle cells and pericytes. Age-related morphological changes are in most of cases organ-specific and include microvascular wall thickening and collagen deposition that affect the basement membrane, with the consequent perivascular fibrosis. Data from experimental models indicate that decreased nitric oxide (NO) bioavailability, caused by impaired eNOS activity and NO inactivation, is one of the causes responsible for age-related microvascular endothelial dysfunction. Consequently, vasodilatory responses decline with age in coronary, skeletal, cerebral and vascular beds. Several therapeutic attempts have been suggested to improve microvascular function in age-related end-organ failure, and include the classic anti-atherosclerotic and anti-ischemic treatments, and also new innovative strategies. Change of life style, antioxidant regimens and anti-inflammatory treatments gave the most promising results. Research efforts should persist to fully elucidate the biomolecular basis of age-related microvascular dysfunction in order to better support new therapeutic strategies aimed to improve quality of life and to reduce morbidity and mortality among the elderly patients. Keywords: Endothelial cells, Smooth muscle cells, Endothelial dysfunction, Nitric oxide, Vascular remodelling, Organ-specific ageing Introduction transvascular exchange and fluid economy [8]. Therefore, Vascular ageing is associated with both structural and cell survival depends on adequate microvascular perfusion functional changes that can take place at the level of [8]. The architecture and the biophysical behavior of the endothelium, vascular smooth muscle cells and the flowing blood strongly influence microvascular function. extracellular matrix of blood vessels [1]. Age, hypertension, Morphologically, the microcirculation is constituted from diabetes, smoking and plasma low density lipoprotein vessels <300 μm in diameter [8]. Therefore, it includes cholesterol level are determinant risks of arterial stiffness arterioles, capillaries, and venules (Figure 1). Alternatively, [2,3]. A relevant age-related vascular change is a progressive a physiological definition based on vessel function rather myointimal thickening [4,5]. Similarly to that observed than diameter or structure has been proposed [9]. By this in large vessels, age-related increase of microvascular tone definition, vessels that respond to an increase of pressure leads to a progressive myogenic hypertrophic remodelling by a myogenic reduction in lumen diameter are consid- of small arteries, due to the increased distending pressure ered part of the microcirculation [9]. Consequently, be- acting perpendicularly on the vascular wall [6]. Micro- sides endothelial cells, also vascular smooth muscle cells vascular alterations play an important role in ageing- (VSMCs) and pericytes must be included in the micro- associated end-organ damage [7]. In fact, microcirculation vascular cell population. Although the primary function is provides the interface for tissue delivery of oxygen and to optimise the nutrient and oxygen supply, microcircula- nutrients, removal of waste products and carbon dioxide, tion is relevant in order to avoid large hydrostatic pressure fluctuations causing disturbances in capillary exchange and an overall peripheral vascular resistance [10]. An im- * Correspondence: [email protected] portant role in regulating tissue fluid balance and in Department of Biomedicine and Prevention, Institute of Anatomic Pathology, Tor Vergata University, Via Montpellier, Rome 00133, Italy © 2014 Scioli et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Scioli et al. Vascular Cell 2014, 6:19 Page 2 of 15 http://www.vascularcell.com/content/6/1/19 Figure 1 Schematic representation of microcirculation components. The microcirculation is a network of small blood vessels, including arterioles, venules and capillaries. Blood flows from the arteries into the arterioles and then pass into the venules across true capillaries or throughfare channels and metarterioles (arteriovenous bypass). The precapillary sphincter, made of smooth muscle cells, controls blood flow into the true capillaries. As blood travels through the capillaries, plasma proteins and fluid enter the interstitial space according to hydrostatic and osmotic pressure gradients. Most of the fluid is reabsorbed into the post-capillary venules, while a fraction enters to the lymphatic circulation for its return to the blood circulation. maintaining osmotic and hydrostatic pressures is played main component of ROS is the superoxide anion (O2-), by the lymphatic system (Figure 1), that comprises a one- which for its high cytotoxic activity is transformed quickly way transport for fluid and proteins by collecting them into hydrogen peroxide (H2O2) by superoxide dismutase from the interstitial space and returning them to the blood (SOD). The H2O2 is transformed in H2O by two enzymes, circulation [11]. This review focuses the attention on the catalase and glutathione peroxidase (GPx) [16]. biomolecular and pathophysiological mechanisms under- As reported, with ageing H2O2 production is enhanced lying age-related microvascular alterations and the [17], leading to the increase of mitochondrial H2O2 and importance of new therapies to prevent end-organ O2- generation, cumulative DNA damage and cellular damage associated with microvascular dysfunction. senescence [18-20]. Moreover, mitochondria are not only targets for ROS but also significant sources of ROS, Biomolecular mechanisms involved in age-related which under certain conditions may stimulate NAD(P)H microvascular dysfunction oxidases [12]. In fact, many studies demonstrated the Reactive oxygen species and oxidative stress principal role of NAD(P)H oxidase activity in aged- The primary mechanism involved in ageing-associated mediated ROS generation in mouse models [21-23] and microvascular dysfunction is the oxidative stress, a state in the improvement of endothelial function by the inhib- which the generation of reactive oxygen species (ROS) ition of NAD(P)H oxidase or scavenging of O2- [24,25]. exceeds the antioxidant defense systems, resulting in In particular, it has been reported that NAD(P)H oxidase cellular dysfunction and apoptosis [12]. Physiologically, 4 is involved in O2- formation and cellular senescence ROS are involved both in the maintenance of steady in ageing, and its inhibition counteracted oxidative vessel wall conditions and in the vascular response to stress in pulmonary and kidney arteries of aged rats, as altered flow or pressure settings [12]. Vascular cells com- well as in lungs of aged mice [26-28]. prise different sources of ROS, including enzymatic activity of NAD(P)H oxidase, xanthine oxidase (XO), uncoupled Nitric oxide endothelial nitric oxide (NO) synthase (eNOS), cytochrome In mammals, nitric oxide (NO) is produced by a family P450 and the mitochondrial respiratory chain [13-15]. The of enzymes, named nitric oxide synthases (NOSs), that Scioli et al. Vascular Cell 2014, 6:19 Page 3 of 15 http://www.vascularcell.com/content/6/1/19 catalyse the production NO from L-arginine. NO is an overexpression caused vascular senescence by mitochon- important cellular signalling molecule that regulates vaso- drial and NADPH-dependent superoxide generation [18]. dilatation, insulin secretion, airway tone, and peristalsis, This mechanism was attenuated by mitochondrial electron and is involved in angiogenesis and neural development transport chain or angiotensin type 1 receptor inhibitors [29]. The family of enzymes NOS comprises three iso- [39,40]. Moreover, the infusion in rats of angiotensin II forms: neuronal NOS (nNOS/NOS1), inducible NOS induced microvascular lesions in various vascular beds that (iNOS/NOS2) and endothelial NOS (eNOS/NOS3) [29] resemble arteriolosclerosis [41]. The blocking of nitric oxide eNOS constitutively produces NO in endothelial cells and synthesis also induced renal microvascular disease [42]. physiologically contributes to the control of vascular tone. It is well known that angiogenesis and wound healing Instead iNOS is activated by bacterial lipopolysaccharide, are reduced with ageing [43]. In fact, vascular endothelial cytokines, and other inflammatory agents, determining an growth factor (VEGF)-induced angiogenesis is attenuated abnormal production of NO. Due to its affinity to protein- in aged rats and rabbits [44,45]. In aged mice and in cul- bound iron, NO can inhibit key enzymes that contain tured human microvascular endothelial cells aged by iron in their catalytic centers. These include iron–sulfur progressive passaging, the expression of the tissue inhibi- cluster-dependent enzymes (complexes I and II) involved tor of metalloproteinase-2 (TIMP-2) is increased [46], and in mitochondrial electron transport, ribonucleotide reduc- correlated with an attenuated capacity of endothelial cells tase (the rate-limiting enzyme in DNA replication), and to degrade extracellular matrix, a process required for cis-aconitase (a key enzyme in the citric acid cycle) [29]. angiogenesis [46]. As discussed above, microvascular dysfunction is mainly Taken together these findings suggest the existence of a induced by the over-production and release of O2-, which complex biomolecular mechanism involved in age-related cause NO breakdown. In fact, NO inactivation is due to vascular dysfunction that leads to oxidative stress, vascular its reaction with O2- to form the potent oxidant peroxyni- remodelling and endothelial dysfunction. This altered sig- trite (ONOO ) [30]. This compound can cause oxidative nalling, in endothelial cells, causes the activation of NF-kB damage, nitration, and S-nitrosylation of biomolecules in- and a consequent abnormal gene transcription, including cluding proteins, lipids, and DNA single-strand breakage the enhancement of cellular adhesion molecule expres- following the poly-ADP-ribose polymerase (PARP) activa- sion, such as intercellular adhesion molecule-1 (ICAM-1), tion [31-33]. The increase of nitration was demonstrated vascular cell adhesion molecule-1 (VCAM-1), E-selectin, in the sarcoplasmic reticular Ca-ATPase isolated from the and inflammatory cytokine secretion [47-49]. This process skeletal muscle of old rats [34]. The scavenging of NO by determines the leukocyte recruitment and extravasation as O2- was also demonstrated in coronary microvascular also demonstrated in the vascular wall of aged rabbits [50]. endothelial cells of old rats, in which the reduction of A schematic representation of age-related biomolecular eNOS expression was accompanied with an increased alterations in microcirculation is reported in Figure 2. O2- production and attenuated vasodilator responses [35]. Coronary arterioles of aged rats displayed an increased Structural and functional microvascular alterations iNOS activity and ONOO production, as well as a de- involved in ageing creased eNOS expression [36]. The same alterations have Arteriolosclerosis been also described in elderly [36]. Microvascular disease is also referred as an impairment of Moreover, oxidative stress can convert eNOS from a flow-induced dilatation of arterioles, defined arteriolo- NO-producing enzyme to an enzyme that generates O2-. sclerosis [51]. Arteriolosclerosis is due to stiffening, with This process is named eNOS uncoupling. Mechanisms loss of elasticity, of arterioles and must be distinguished implicated in eNOS uncoupling include oxidation of the from arteriosclerosis, a hardening with loss of elasticity critical NOS cofactor BH , depletion of L-arginine, and of medium or large arteries, and from atherosclerosis, a accumulation of endogenous methylarginines [29]. stiffening of an artery specifically due to an atheromatous plaque. Arteriolosclerosis is characterised by intimal thick- Age-related signal alterations in vascular cells ening, vascular smooth muscle cell proliferation, and It has been demonstrated that endothelin-1 and angioten- extracellular matrix deposition, resulting in an increased sin II (potent vasoconstrictors) pathways are involved in media-to-lumen ratio, and later by the replacement of the age-related endothelial oxidative stress [18]. In particular, vascular smooth muscle cells by areas of fibrosis and ageing induced endothelin-1 overexpression, resulting in cell loss [51]. Consequently, arteriolosclerosis may have vascular remodelling and endothelial dysfunction in mice a key role in mediating the development of chronic kidney [37]. In addition, it has been reported the involvement disease, vascular dementia, stroke and coronary heart dis- of endothelin-1 in eNOS downregulation in pulmonary ease [51]. Hyaline arteriolosclerosis refers to a thickening artery endothelial cells of fetal porcine [38]. As concerning of the wall of arterioles by the deposition of homogeneous angiotensin II, it has been documented that in ageing its pink hyaline material and can involve multiple organs, Scioli et al. Vascular Cell 2014, 6:19 Page 4 of 15 http://www.vascularcell.com/content/6/1/19 Figure 2 Schematic representation of biomolecular changes in age-related microvascular dysfunction. Oxidative stress plays a pivotal role in endothelial and myocitic impaired function. including brain (Figure 3). Structural and functional alter- and exhibits an increased uptake of modified low-density ations described above involve all microvascular compo- lipoprotein (LDL) and decreased NO production [58]. For nents, including endothelial cells, pericytes and smooth example, as documented in aged rats, important structural muscle cells. Below are summarised the principal features changes of brain capillaries were found: thickening of the of age-related microvascular cell changes. basal lamina and the thinning of endothelial cells [59]. Some suggestthatthis phenomenonis due to aloss Endothelial cells of endothelial cells together with a lengthening of As a consequence of the alteration in the expression and/ the remaining ones to allow nutrients to diffuse [60]. or activity of eNOS, upregulation of iNOS, and increased Mophological alteration of aged endothelium was observed formation of ROS and ONOO , endothelial cells undergo also in sinusoids of human aged liver, where thickening to cumulative DNA damage that promotes senescence of the sinusoidal endothelium was associated with the and apoptosis [52]. As described above, the age-related deposition of basal lamina and collagen [61]. In the kidney decline of endothelial function becomes manifest through of aged rats the number of proliferating endothelial cells a reduced regenerative and angiogenic capacity, and an was decreased compared with young rats. In addition, altered expression of adhesion molecules regulating the VEGF expression strongly decreased with ageing in the interaction of circulating factors with immune system endothelium of the outer and inner medulla, suggesting a cells [53,54]. reduced angiogenic activity [62]. The attenuated capacity of the endothelium to regen- erate is partially a consequence of an impaired secretion Smooth muscle cells and pericytes of and/or sensitivity to growth factors [55]. Recently, the As discussed above, in ageing, upregulation of pro-oxidants regeneration of the endothelium by bone marrow-derived and downregulation of antioxidants results in an imbalance circulating progenitor cells has gained particular attention, leading to ROS increase [63-65] and to the development of because the number of circulating endothelial progenitor vascular dysfunction in both animal models and in humans cells (EPCs) decreases with age and is thought to reflect the [66]. In old rats, a significant increase in O2- was observed attenuated mobilization of these cells from the bone mar- in the vascular wall [67], and was associated with an row [56]. Moreover, EPCs from older subjects have a re- increase in NAD(P)H oxidase activity [36,64,68-70]. It has duced capacity to engraft [57]. Some studies suggest that been also reported that Angiotensin II pathway plays an the regenerated endothelium is functionally impaired [57] important role in age-related smooth muscle cell oxidative Scioli et al. Vascular Cell 2014, 6:19 Page 5 of 15 http://www.vascularcell.com/content/6/1/19 Figure 3 Age-related changes of brain microvasculature. Post-mortem (myocardial acute infarction) histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed cerebral tissue. PAS staining of human brain gray matter, showing normal capillaries and arterioles in a young (A,C) compared to concentrically thickened microvessels in an aged man (B,D) mostly due to hyalinization (pink staining). Masson's trichrome staining shows normal microvessel in a young (E) and perivascular deposition of collagen (blue staining) around capillaries in an aged man (F). Immunohistochimical analysis for α-SMA shows normal arteriole in a young (G) and concentrically thickened arteriole due to an altered proliferation of smooth muscle cells in an aged man (H). Magnification 40×. stress by eliciting NAD(P)H oxidase activity [71]. In fact, can also induce the activityofiNOSthrough theNF-kB Angiotensin II stimulation induced the NAD(P)H oxidase- pathway under inflammatory conditions [64], as also dependent O2- production, stimulating NF-κB signalling reported in aged Macaca mulatta, rats [64,74] and mice in senescent VSMCs [72]. Similarly to endothelial cells, [75]. As already reported, vascular ageing is also associated VSMCs of old rats in response to cytokines showed higher with a progressively reduced NO bioavailability. Since ICAM-1 level compared with newborn rats [73]. VSMCs VSMCs are important targets for endothelium-derived Scioli et al. Vascular Cell 2014, 6:19 Page 6 of 15 http://www.vascularcell.com/content/6/1/19 NO, this reduction causes an impairment of endothelium- Lymphatic vessel alterations dependent vasodilation [76]. In addition, the in vitro Lymphatic system begins when the plasma fluid and response of VSMCs to NO and β-adrenoreceptor stimula- proteins, that are forced out by arterial capillaries into tion is decreased by ageing, and such changes may the interstitial space (Figure 1), are collected into the contribute to impairment of endothelium-independent lymphatic capillaries, which are freely permeable to vasodilation in the elderly [76,77]. Consequently to macromolecules [90]. So, the main function of lymphatic age-related oxidative stress and impaired signalling trans- system is to maintain osmotic and hydrostatic pressures duction, VSMCs undergo to phenotypic alteration, prolifer- within the tissue space. It consists of capillaries (10-60 μm ation, migration, dedifferentiation and extracellular matrix in diameter) that drain lymph into the collecting vessels remodelling, as reported in coronary resistance arterioles that contain also smooth muscle. The fluid pass through of old rats [5]. The series of events lead to increased vessel several clusters of lymph nodes and then into larger wall thickness, inflammation, and vulnerability to the de- trunks, which in turn lead into the ducts, that return velopment of vascular dysfunction [64,78]. VSMCs lose lymph back into the bloodstream [11]. their specialised or differentiated properties and become Spontaneous contractions of smooth muscle cells in proliferative and highly motile [5,79]. Extracellular matrix the wall of lymphatic vessels are necessary to maintain reorganization occurs with ageing, such as collagen increase effective lymph flow whereas proper functioning of lymph- and elastin fragmentation [80]. These changes in the atic endothelial cells is necessary to regulate lymphatic relative content and organisation of collagen and elastin contractility [91]. The basic self-regulatory mechanisms result in increased fibrosis and contribute to the stiffening controlling lymph flow in lymphatic vessels is realised of the vascular wall [81]. It may be due to alternative through the sensitivity of their muscle cells to levels of signal transduction pathways revealed by the ability of the stretch and of their endothelial cells to levels of the shear older cells to respond to inhibitors, such as transforming stress [91]. Nitric oxide plays an important functional role growth factor-β1, or to altered interactions with the extra- in coordinating the lymphatic contractile cycle [92] and in cellular matrix resulting from age-associated shifts in fine tuning lymphatic contractions to different levels of integrin expression [54]. Both b1 integrin, adhesive basal luminal flow [93]. Zhdanov and Zerbino reported interactions with fibronectin and α-smooth muscle actin ageing-related changes in morphology of various human (α-SMA) are also major players in VSMC stiffening [82]. lymphatic networks in the early 1960s [90,94,95]. They Pericytes, the mural cells on capillaries, play an important observed a reduction in the number of lymphatic capil- role in vessel stabilisation, by regulating endothelial cell laries (nonmuscular initial lymphatics) through all of the proliferation and preventing capillary withdrawal [83-85]. body and the presence of specific “varicose bulges,” which Alterations in these cells with ageing also might contribute exist in muscular lymphatic vessels. It has also been to the development of age-related morphological and reported that aged thoracic duct showed signs of lipid physiological abnormalities of the microvasculature. In accumulation, thickening, and fibrosis [90,96]. fact, microvascular ageing is characterised by changes Recently, some authors reported changes in orientation in peripheral capillaries, including vessel broadening, and investiture of muscle cells in mesenteric lymphatic and thickening of the basement membrane, as well as vessels in aged rats [90,91]. It has been postulated that altered length and orientation of desmin filaments in in elderly the decrease of accessory muscle elements pericytes [86]. These changes can determine a reduced surrounding lymphatic valve may limit the ability of pericyte–endothelial cell contact, destabilisating capillaries lymphatic vessels to adapt their contractility to various [86]. In addition, a reduction in pericyte number in aged preload/afterload challenges with subsequent formation capillaries was also reported [87]. In the brain capillaries of lymph stasis and potential spread of pathogens and of elderly the decrease in pericyte coverage was reported immune cells in direction opposite to the direction of [88]. It has been also documented that in the retina of the normal lymph flow [90]. In addition, the thin-walled old rats, ageing induced the broadening of peripheral low muscle cells investiture zones in aged rats may be capillaries and terminal venules, as well as thickening transformed to aneurysm-like formations “varicose bulges”, of basement membranes [86]. In the retina of old rats which can be ideal places for formation of low-velocity was reported a shift from a pericyte phenotype toward turbulent lymph flow and accumulation of various mol- an arteriolar smooth muscle cell–like phenotype. It was ecules, pathogens, and cancer cells [90]. Some studies associated with an increase in calponin labelling of reported a reduced lymph flow in aged animals in vivo arterioles, thickness of basement membranes, and increased [97,98]. Ageing severely altered contractility of the toracic focal adhesions in arteriolar walls [86]. Moreover, in skeletal duct through weakening of lymphatic contractions and muscle of old mice, the muscular regenerative capacity complete depletion of their shear/nitric oxide (NO)- of pericytes is limited, and they produce collagen and dependent regulation [98]. It has been demonstrated contribute to fibrous tissue depositing [89]. that ageing severely altered NO-dependent regulation of Scioli et al. Vascular Cell 2014, 6:19 Page 7 of 15 http://www.vascularcell.com/content/6/1/19 thoracic duct contractions with an impaired eNOS function to overexpression of the transcription factors: serum and an ageing-associated shear-independent NO release in response factor (SRF) and myocardin [105]. In the duct due to iNOS activation [98]. Non-specific nitric addition, SRF and myocardin may also regulate con- oxide synthase (NOS) blockade restored the contraction tractile proteins in VSMCs, thus altering normal vessel [98]. These findings provided functional consequences of physiology [106]. ageing in lymphatic contractility and the dysfunctional responses of smooth muscle cells and endothelium in Liver ageing-induced alterations [98]. Age-related changes in the human hepatic sinusoidal endothelium, termed pseudocapillarisation, have been recently described and they contribute to the impairment Age-related changes of end-organ microvasculature of hepatic function [107]. Blood clearance of a variety As a consequence of the age-related alterations in the of waste macromolecules takes place in liver sinusoidal expression and/or activity of eNOS, upregulation of iNOS, endothelial cells (SECs) [108]. These cells are unique increased formation of ROS and ONOO-, and extracellular endothelial cells in both their architecture and their matrix remodelling, vasodilatory function is impaired and function. The sinusoids are the exchange vessels of the an excessive capillary pressure with consequent hyperfiltra- liver, and the SECs are distinguished by extensive fenes- tion, protein leakage, edema formation and tissue damage trations organized into sieve plates, a lack of a basement occur. In small arteries and arterioles, which have a relative membrane, and low junctional expression of CD31 [108]. higher wall thickness, changes in tone and circumferential The SEC architecture, including open fenestrations and shortening have an enhanced effect on lumen diameter, weak junctional association between cells, provides a resulting in a blood flow decline in many organs [7]. We dynamic filtration system with low perfusion pressure describe the main alterations that characterise the age- that enables nutrients and macromolecular waste to related end-organ damage. pass freely to hepatocytes for efficient metabolism [108]. The maintenance of SEC phenotype is a critical Brain process that requires both autocrine and paracrine cell Cognitive dysfunction from lower perfusion and micro- signalling [108]. Recent studies indicate that fenestra- vascular fibrohyalinosis is the most common type of tions are maintained by constitutive VEGF-stimulated microvascular damage in the elderly [99]. Atherosclerosis NO generation in SECs and surrounding cells [109]. In in elderly people also coincides with massive microvascular response to ageing [110], SECs dedifferentiate into a more fibrosis, which contributes to the development of white regular endothelium, hence the term capillarisation or matter lesions, myelin rarefaction or demyelination, gliosis, pseudocapillarisation. The hallmarks of capillarisation apoptosis and regressive astrocytic changes [99-101]. Thick- are SEC defenestration, development of a laminin-rich ening of small vessels was associated with diffuse white basement membrane, junctional expression of CD31 matter lesions in elderly [102]. Reduced pericyte–endothe- and protein nitration, in a mechanism involving NAD(P)H lial cell contact also occurs [86]. oxidase–generated ROS [108]. In addition, sinusoidal Brain arteriolosclerosis is a subtype of cerebrovascular stellate cells are also induced to overexpress a laminin and pathology characterised by concentrically thickened arte- collagen matrix that contributes to fibrosis [111]. rioles due to an altered proliferation of smooth muscle In autoptic studies of older human subjects, independ- cells and excessive extracellular matrix deposition [103], ently from the presence of systemic diseases or hepatic as also shown in our histological study (Figure 3). pathologies, pseudocapillarisation occurs from increased Cerebral amyloid angiopathy (CAA) is another micro- peri-sinusoidal expression of von Willebrand’sfactor, vascular pathology associated with ageing and results from CD31 and collagen I and IV, resulting in a thickening and deposition of β-amyloid in the media and adventitia of defenestration of the liver sinusoidal endothelium and small arteries and capillaries of the leptomeninges and deposition of basal lamina in the extracellular space of cerebral cortex and is a major cause of lobar intracerebral Disse [61,107], as also shown in our histological study hemorrhage and cognitive impairment in the elderly [104]. (Figure 4). In addition, it has been reported an endothelial CAA is present in nearly all brains with Alzheimer disease, upregulation of ICAM-1 [61]. Transmission electron mi- suggesting a common β-amyloid-based pathogenesis for croscopy study revealed a significant age-related thickening these diseases. However, despite the close molecular of the sinusoidal endothelium, with loss of fenestrations relationship between the two diseases, CAA remains a [61]. Loss of fenestrations leads to impaired transfer of clinically distinct entity from Alzheimer disease [104]. lipoproteins from blood to hepatocytes. This provides a The accelerated β-amyloid vascular deposition in mechanism for impaired chylomicron remnant clearance CAA seems to be caused by a transcriptional deregu- and postprandial hyperlipidemia associated with old lation of the lipoprotein receptor LRP in VSMCs due age [112]. Scioli et al. Vascular Cell 2014, 6:19 Page 8 of 15 http://www.vascularcell.com/content/6/1/19 Figure 4 Microscopic aspects of human liver pseudocapillarisation. Post-mortem (myocardial acute infarction) histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed liver tissue. Masson's trichrome staining shows the central vein and pericentral hepatocytes of young (A) and old liver (B) with perisinusoidal collagen deposition (blue staining). CD31 immunostaining of young (C) and old liver (D) with an increased sinusoidal protein expression. Magnification 20×. Heart and platelets [119]. Taken together, these findings suggest Ageing is also associated with functional changes of that arteriolar changes, induced by ageing-related oxidative the coronary microvasculature [113]. An important stress, impairs the vasoactive function of the coronary mechanism that contribute to the local regulation of vessels in ageing. myocardial blood flow is the flow (shear stress)–induced NO mediated dilatation of small coronary arteries and ar- Kidney and skin terioles [114]; so ageing, that impairs NO synthesis/release With ageing, a degenerative process occurs with the in the endothelium (as described above), determines a appearance of glomerular lesions, as a thickening of the vasodilatory dysfunction also in rat coronary arterioles glomerular basement membrane and Bowman’s capsule [115]. It was also reported an increased breakdown of NO [120], parallel to glomerulosclerosis, interstitial fibrosis due to an augmented arteriolar production of O2- [116]. and progressive proteinuria [121]. Biochemical studies Moreover, in isolated coronary arterioles of old rats, evidenced the age-related increase of collagen and decrease with an impaired flow-induced dilatation, O2- and in glycosaminoglycans, particularly of heparan sulphate ONOO- production increased both in endothelial and [122]. Ultrastructural studies, conducted in our laboratory, VSMCs [36]. In addition, eNOS and SOD activity were documented a marked thickening of the glomerular base- impaired, whereas NAD(P)H oxidase and iNOS were up- ment membrane in old rats (Figure 5A-B). In addition, regulated. [36]. Aged human and rabbit small coronary young rats perfused with cationized ferritin in vivo showed vessels show a marked increase of myocardial interstitial a regular distribution of these molecules, along the in- collagen, with α-SMA and TGFβ-1 negative fibroblasts ternal and external lamina rara of the glomerular base- and VCAM-1 positive microvessels without macrophages ment membrane (Figure 5C). In the old rats, ferritin was [117,118]; these findings support the close link between present only along the internal lamina rara (Figure 5D), endothelial dysfunction and age-related fibrosis [117,118]. suggesting that the age-related loss of anionic charged of The impaired coronary endothelial function may result in heparan sulphate molecules is responsible for age-related adverse clinical events because of the increased vascular proteinuria, also reported in human. In the kidney of aged and perivascular recruitment of neutrophils, macrophages, rats, the glomerular and peritubular capillary loss Scioli et al. Vascular Cell 2014, 6:19 Page 9 of 15 http://www.vascularcell.com/content/6/1/19 Figure 5 Ultrastructural aspects of age-related changes in rat kidney microvessels. Glomerular basement membrane of kidney in young (A) and old rat (B), that shows the characteristic thickening of capillary wall. Magnification 5000×. Cationized ferritin distribution on glomerular basement membrane of young (C) and old rat kidney (D). Magnification 30000×. correlates with alterations in VEGF and TSP-1 expression decrease in eNOS expression in peritubular capillaries and also with the development of glomerulosclerosis and [127]. In addition, it has been reported that ageing induced tubulointerstitial fibrosis, suggesting an impaired angio- oxidative stress in kidney and the attenuation of redox genesis associated with progressive loss in renal microvas- status can ameliorate microvascular function [128]. Renal culature [62]. The mechanism of capillary loss in oxidative stress was associated with an increase in aged kidney has not been fully understood. Angiosta- ONOO , NO and ROS levels, as well as iNOS activity tin is a potent inhibitor of angiogenesis in vivo. In [129]. Treatment with an antioxidant reduced the age- aged rats angiostatin production is increased, as well related renal dysfunction [129]. Moreover, in aged rats, as the activity of cathepsin D, the enzyme for angios- NF-κB activation has been reported to contribute to the tatin production [123]. In addition, NO availability is accumulation of oxidative stress [130]. decreased and cathepsin D activated, suggesting a pos- Structural and functional alterations of the skin during sible correlation between the increase of angiostatin the ageing process are due to some complex mechanisms, production, capillary loss and interstitial damage in determined by intrinsic and extrinsic factors, which act aged rat kidney [123]. NOS inhibition by L-NAME pro- synergistically [131]. Collagen fibers become thinner and duced a stronger vasoconstriction in renal vessels of change their aspect; in the deep dermis they become more old compared with young rats [124,125], suggesting fibrous. Thickened microvessels can be recognised by the that endogenous NO production is necessary for the increased intensity of the vascular PAS positive-diastase control of renal circulation. Moreover, post-mortem an- resistant staining, and by the perivascular collagen depos- giograms and histology studies, in elderly, showed wall ition (Figure 6). Elastic fibers show the tendency of frag- thickening and narrowing of the vascular lumen of af- mentation, with a pathological assembly [131,132]. With ferent arterioles, an alteration mainly depending on ageing, a progressive reduction of dermis vasculature is VSMC proliferation [126]. present, due to a reduction in the number and size of Tubulointerstitial fibrosis, in aged rats, was characterised vascular vessels [131]. Age-related decrease in the number by tubular injury and focal tubular cell proliferation, myofi- of dermal blood vessels is suggested to be due to an broblast activation, macrophage infiltration with increased impairment of VEGF signalling [133]. In addition, it has immunostaining for the adhesive proteins osteopontin been reported that eNOS activity is required for full and ICAM-1, and collagen IV deposition, as well as a expression of reflex cutaneous vasodilation, and its Scioli et al. Vascular Cell 2014, 6:19 Page 10 of 15 http://www.vascularcell.com/content/6/1/19 Figure 6 Ageing in skin microcirculation. Histology studies on paraffin-embedded sections (5 μm thick) of formalin-fixed skin of healthy subjects. Masson's trichrome staining shows collagen distribution (blue staining), around microvessels, in young (A) and old dermal skin (B). PAS staining shows hyaline deposits (pink staining), around microvessels, in young (C) and old dermal skin (D). CD31 immunostaining of young (E) and old dermal skin (F) showing the descrease of capillaries associated with ageing process. α-SMA immunostaining of young (G) and old dermal skin (H) showing the proliferation of VSMCs around aged microvessels. Magnification 40×. Scioli et al. Vascular Cell 2014, 6:19 Page 11 of 15 http://www.vascularcell.com/content/6/1/19 impairment in aged skin is associated with alterations Ascorbate is essential for normal endothelial function in NO signalling [134], increase of oxidative stress and [155] and prevents microvascular dysfunction and H2O2- upregulation of arginase [135]. mediated injury in cultured microvascular endothelial cells [144]. Other natural substances, such as aged garlic extract and resveratrol, have been documented to minimise oxida- Therapeutic targeting of microvascular ageing tive stress and to stimulate endothelial NO generation, Being assumed that microvascular dysfunction plays a key suggesting that antioxidant regimens can be efficacy to role in age-related end-organ failure, several therapeutic counteract adverse clinical effects of age-related micro- attempts have been suggested. We summarised the most vascular endothelial dysfunction [74,75,156]. In vitro studies diffuse anti-atherosclerotic and anti-ischemic treatments suggest that the molecular mechanisms of resveratrol- and more anti-ageing innovative strategies. mediated vasoprotection involve NF-kB inhibition, upreg- ulation of eNOS and antioxidant enzyme levels, and the Changes of lifestyle, anti-atherosclerotic and anti-ischemic prevention of oxidative stress–induced apoptosis [157,158]. treatments Resveratrol supplementation may confer a significant vaso- Due to a high burden of cardiac risk factors and coronary protection in elderly humans [63]. atherosclerosis in subjects with angina and no obstructive coronary artery disease, lifestyle changes to modify risk factors are fundamental [136,137]. Cardiac rehabilitation Novel anti-inflammatory therapies is recommended for those patients who have limited Vascular ageing is associated with deregulation of TNF-α physical activity; increased exercise capacity is related to expression [36,159]. TNF-α is a master regulator of vascular the amelioration of atherosclerotic disease symptoms [138]. inflammatory cytokines, chemokines and adhesion mole- Statins may improve endothelial function by lipid- cules. TNF-α plasma level increases with ageing and corre- independent anti-inflammatory and antioxidant properties lates with morbidity and mortality in the elderly patients and the capacity to restore microvascular NO availability [160,161]. Consequently an anti-TNF-α treatment (i.e., with [139]. Angiotensin-converting enzyme inhibitors as well as etanercept, which binds and inactivates TNF-α) may exert angiotensin-renin blockers [140] have been shown to im- vasoprotective effects, including a reduction of endothelial prove endothelium-dependent relaxation of coronary arter- cell apoptosis and the downregulation of NAD(P)H oxi- ies by increasing NO availability [141]. Upregulation dases activity [162]. Pharmacological inhibition of the poly of arginase has emerged as an important factor con- (ADP-ribose) polymerase (PARP) pathway also represents tributing to reduce NO production by competing with a novel therapeutic target to improve ageing-associated endothelial NO synthase for the common precursor cardiovascular dysfunction [163]. substrate L-arginine [142]. Arginase inhibitors may in- duce long-term improvement of microvascular func- tion and limitation of myocardial injury following Conclusions ischaemia–reperfusion [143]. Ageing elicits several structural and functional changes in the microvasculature. Reactive oxygen species and Antioxidant therapy the concomitant oxidative and nitrosative stress play an Some works focused the attention on antioxidant agents important role in the process of ageing-related micro- that can prevent or reduce the progression of end-organ vascular dysfunction, affecting vascular function as well microvascular dysfunction [144]. Antioxidants and free as signalling transduction and gene expression. Although radical scavengers such as N-acetyl-cysteine (NAC), a significant progress has been achieved in describing the ascorbic acid and Propionyl-L-carnitine (PLC) showed a intrinsic age-related alterations of microvascular function, clinical efficacy in patients with endothelial dysfunction the age-related decline in endogenous antioxidant mecha- [145-149]. NAC, a derivative of cysteine, and ascorbic nisms, angiogenesis, endothelium-dependent vasodilation acid induced beneficial effects on oxidative stress and vas- and microvascular permeability remains to be fully cular dysfunction [145-147]. PLC is an ester of L- assessed. Increased knowledge may lead to new therapies carnitine, that is required for the transport of fatty acids targeting microvascular dysfunction and to improve clinical into the mitochondria [150]. PLC has been reported to outcome. A key observation is that new therapeutic oppor- modulate NF-kB activity in vascular cells [151] and to re- tunities aimed to favour microvascular function are also duce age-related microvascular dysfunction and myocar- associated with ameliorated organ function. An appropri- dial remodelling, including adhesion molecule expression ate control of ageing process, in particular of oxidative [152]. In addition, it has been reported that PLC coun- stress, can clarify the efficacy of many pharmacological or teracts membrane lipid peroxidation and reduces post- nutritional approaches in order to delay the onset of age- ischemic endothelial dysfunction [153,154]. dependent microvascular disease. Scioli et al. Vascular Cell 2014, 6:19 Page 12 of 15 http://www.vascularcell.com/content/6/1/19 Competing interests 21. 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Vascular Cell – Springer Journals

Published: Sep 16, 2014

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