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Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 National Science Review 5: 933–946, 2018 REVIEW doi: 10.1093/nsr/nwx153 Advance access publication 26 December 2017 MULTIDISCIPLINARY 1 1 1 1,2,∗ Yue Han , Kai Huang , Qing-Ping Yao and Zong-Lai Jiang ABSTRACT Vascular remodeling is a common pathological process in cardiovascular diseases and includes changes in cell proliferation, apoptosis and differentiation as well as vascular homeostasis. Mechanical stresses, such as shear stress and cyclic stretch, play an important role in vascular remodeling. Vascular cells can sense the mechanical factors through cell membrane proteins, cytoskeletons and nuclear envelope proteins to initiate mechanotransduction, which involves intercellular signaling, gene expression, and protein expression to result in functional regulations. Non-coding RNAs, including microRNAs and long non-coding RNAs, are involved in the regulation of vascular remodeling processes. Mechanotransduction triggers a cascade reaction process through a complicated signaling network in cells. High-throughput technologies in combination with functional studies targeting some key hubs and bridging nodes of the network can enable the prioritization of potential targets for subsequent investigations of clinical translation. Vascular mechanobiology, as a new frontier field of biomechanics, searches for principles of stress-growth in vasculature to elucidate how mechanical factors induce biological effects that lead to vascular remodeling, with the goal of understanding the mechanical basis of the pathological mechanism of cardiovascular diseases at the cellular and molecular levels. Vascular mechanobiology will play a unique role in solving the key scientific problems of human physiology and disease, as well as generating important theoretical and Institute of clinical results. Mechanobiology & Medical Engineering, Keywords: mechanobiology, vascular remodeling, cardiovascular disease, mechanotransduction, School of Life endothelial cell, vascular smooth muscle cell, nuclear envelope, microRNA Sciences & Biotechnology, Shanghai Jiao Tong volves the flow of blood, deformation of blood cells INTRODUCTION University, Shanghai and blood vessels, and interaction between blood Cardiovascular disease is one of the most serious 200240, China and and vessels, which comprise the rich mechanical health hazards. Elucidation of the pathogenesis of School of Biological mechanisms. Many clinical and experimental studies cardiovascular disease for its prevention is a major Science & Medical have demonstrated that biological, chemical, physi- Engineering, Beijing field of biomedical research [ 1]. Cardiovascular dis- cal, and other factors affect the vascular remodeling Advanced Innovation orders, including hypertension, atherosclerosis and in vivo and in vitro, in which mechanical factors play a Center for Biomedical stroke, are essentially vascular diseases. They have direct and important role. We have selected vascular Engineering, Beihang a common pathogenic mechanism and basic patho- remodeling as a starting point to explore some com- University, Beijing logical process, i.e., vascular wall remodeling, which 100083, China mon modes of pathogenesis for the complex char- includes cardiovascular cell migration, hypertrophy, acteristics of multi-gene, multi-pathogenic factors in proliferation and apoptosis, as well as changes in cardiovascular diseases. Corresponding cell phenotype, morphological structure and func- author. E-mail: Biomechanics studies the deformation and tion . firstname.lastname@example.org movement of living entities, through the organic The human body exists in a mechanical environ- combination of biological and mechanical prin- ment, which influences the biological processes at Received 20 August ciples, to recognize the laws of life processes and every level, including the whole body, organs, tis- 2017; Revised 6 solve scientific issues in the field of life and health. sues, cells and molecules. The cardiovascular system November 2017; Y. C. Fung proposed the stress-growth law in his can be considered a mechanical system in which the Accepted 22 monograph Biomechanics: Motion, Flow, Stress, central position is occupied by the heart, which func- December 2017 and Growth in 1990, which states that remodeling tions as a mechanical pump. Blood circulation in- The Author(s) 2017. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. All rights reserved. For permissions, plea se e-mail: email@example.com Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 934 Natl Sci Rev, 2018, Vol. 5, No. 6 REVIEW of a blood vessel involving growth or resorption cellular signal, and then trigger the cascade reaction of cell and extracellular materials is linked to process, which is known as mechanotransduction. stress in the vessel . The stress-growth law is a fundamental theory that expounds the intrinsic relationship between the most basic form of matter Roles of the cell membrane and movement, mechanical motion, and the highest cytoskeletons in mechanotransduction form, life motion, and guides the transformation of Multiple mechanosensors in the vascular cell biomechanics from mechanics applied to biology to membrane have been reported, including integrins the organic bond of mechanics with biological pro- [9–18], ion channels [19–28], junctional proteins cesses. A qualitative change and the development [29–32], growth factor receptors , receptor ty- of biomechanics are observed. Mechanobiology, as rosine kinases (RTKs) [33,34], G protein-coupled a new frontier field of biomechanics, has increased receptors (GPCRs) [35–39], platelet/endothelial with response to proper timing and conditions. cell adhesion molecule-1 (PECAM-1) [40,41], and Mechanobiology encompasses several broad re- caveolae [37,38,42], as well as membrane lipids search areas and searches for the effects of the [43,44], glycocalyx [45–50], and primary cilia mechanical environment in health, disease or injury, [51,52]. mechanosensitive responses and their mechanisms, The above-mentioned mechanosensors are on inter-relations between mechanics and biological or in the vascular cell membrane. However, in processes, such as growth, adaption, remodeling, the endothelium, the interconnected cytoskeletal and repair, and discoveries related to new diagnostic filaments are also linked to membrane proteins in and therapeutic procedures [4,5]. These studies are every part of the cell. The cytoskeleton is made up of great theoretical and practical significance for our of actin filaments, microtubules and intermediate understanding of the mechanical mechanisms and filaments, providing elastic stiffness and maintaining natural laws of growth and senility of the human the shape and structure of a cell to enable specific system, expounding pathological mechanisms of cellular functions . Different cytoskeletal diseases, and researching and developing new networks have interpenetration and interactions, medicines and technologies for medicine. which combined with specific cross-linking, have an Vascular mechanobiology elucidates the princi- effect on the cellular overall mechanical response. ples of stress-growth in the vasculature, as well as In response to shear stress, AMP-activated protein how mechanical factors induce biological effects to kinase (AMPK) phosphorylation of cortactin, result in vascular remodeling to elucidate the me- followed by sirtuin 1 (SIRT1)SIRT1 deacetyla- chanical basis of blood circulation and the natural tion, regulates the interaction of cortactin and laws of growth and senility of the vasculature and to cortical–actin. This AMPK/SIRT1 co-regulated expound the pathological mechanism of cardiovas- cortactin–F-actin dynamics is need for a sub-cellular cular diseases on cellular and molecular levels. translocation/activation of endothelial nitric oxide synthase (eNOS) and is also atheroprotective . There is ample evidence indicating that cytoskeletal assembly and dynamics respond to different flow VASCULAR CELLS RESPOND TO patterns. Conceivably, mechanical stimuli acting MECHANICAL STRESSES on the cell surface are transmitted to the cytoplasm The blood vascular wall has three mechanical force via cytoskeletal deformations such as intermediate loadings, i.e., shear stress (SS), normal and circum- filament displacement or actin filament deforma- ferential stresses. SS, which acts parallel to the lumi- tion. Direct observation of intermediate filament nal surface of the vessel, is an outcome of fluid viscos- displacement in cells expressing green fluorescent ity and the velocity gradient between adjacent lay- protein has suggested that SS rapidly alters the ers of the flowing blood [ 1,6,7]. The circumferential cytoskeletal mechanics. In addition to its structural stress acts along the vessel wall perimeter to cause roles, the cytoskeleton also regulates gene tran- stretching, resulting in corresponding deformation scription through nucleocytoplasmic shuttling of of the vessel wall, which is termed the circumferen- mechanosensitive transcriptional activators . tial strain. Vascular cells respond to mechanical stresses such as SS and stretch, which can be sensed by cells, Role of the cell nucleus in by regulating the cell signaling pathway, affecting mechanotransduction gene expression and influencing cell functions as a result [6–8]. Through various means, the cells trans- A mechano-vascular proteomic study suggested that form the exocytic mechanical signal into an intra- the proteins of the nucleus envelope (NE) might Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 REVIEW Han et al. 935 Nesprin2 a b c Cyclic stretch Shear stress NPC ONM ECs VSMCs Emerin LaminA/C Nesprin2 LaminA SUNs INM Nuclear Emerin specific LaminA specific Emerin lamins Shear stress motif motif AP-2 TFIID Stat1, 3, 5, 6 LaminA NUCLEUS GEM FOS BCL2L1,IRF1, E2F1, IRF1, E2F1, IRF1, KLF4, Transcription LDLR IFNG, IL4, CCND2 KLF4, SP1 SP1, STAT1 Target factor Cell function genes Cyclic stretch VSMCs proliferation ECs proliferation & apoptosis Figure 1. Schematic diagram of the roles of nuclear envelope proteins in vascular mechanotransduction. (a) A schematic diagram of the putative signaling pathways involved in the effects of nuclear envelope proteins on EC or VSMC functions in response to mechanical stimuli. (b) Low SS represses the expressions of nesprin2 and lamin A, which impacts the activation of transcription factors AP-2, TFIID and Stat1, 3, 5, 6, regulates the mRNA levels of their downstream target genes, and then induces the proliferation and apoptosis of ECs. (c) Pathological cyclic stretch suppresses the expressionof emerin and lamin A/C, which bind to specific motifs in the DNA segments, and decreases the binding of emerin to the promoter regions of E2F1, IRF1, KLF4 and SP1, and the binding of lamin A/C to the promoter regions of E2F1, IRF1, KLF4, KLF5, SP1 and STAT1, eventually inducing VSMC proliferation. and cytoskeleton (LINC) complexes and transmit directly respond to mechanical stimuli and regulate mechanical stresses into the nucleus . Recently, gene expression afterwards [ 56]. All these molecules the role and function of LINC complexes have are implicated in mechanotransduction of SS and gained attention for their involvement in connect- subsequently result in endothelial cell (EC) func- ing the cytoskeleton to the nucleus to transduce me- tional responses, e.g., proliferation, apoptosis, migra- chanical stimuli throughout the cell. tion and permeability. LINC complexes, conserved from yeast to men, The nucleus is the stiffest and largest sub-cellular are composed of both ONM and INM proteins that organelle in most cells, playing an important role in belong to the Klarsicht, Anc-1, and Syne homology storing and managing genetic information and serv- (KASH) domain protein families, as well as Sad1 ing as the site for DNA and RNA synthesis, tran- scription processing, and coordinating the intricate and UNC-84 (SUN) homology domain proteins cellular architecture. Consisting of two lipid bilay- . The acronym KASH originates from the con- ers, namely the inner and outer nuclear membranes servation of the same domain in Klarsicht from D. melanogaster, ANC-1 from C. elegans, and Syne ho- (INM and ONM), NE is the physical barrier be- mology from mammals. Most KASH domain pro- tween the cytoplasm and genome, and ONM is an teins reside in the ONM, and their amino-terminal extension of the rough endoplasmic reticulum (ER) regions are exposed to the cytoplasm and are as- and is connected to INM at the nuclear pore com- sociated with the cytoskeleton, such as actin fil- plex (NPC). INM and ONM delineate the periplas- aments, microtubules, and intermediate filaments. mic space, which is continuous with the ER lumen. The carboxyl termini of KASH proteins contain the INM proteins interact directly with the nuclear lam- KASH domain, which is a 30-amino-acid peptide ina, a specialized meshwork of lamins that constitute typically ending with the conserved motif PPPX or the type V intermediate filament family. The INM PPPT. The N-terminus of KASH proteins extends and ONM are perforated by NPCs that control traf- into the perinuclear space (PNS) and interacts with fic in and out of the nucleus. NPCs mediate the ex- the SUN domain of SUN proteins . The SUN change of different sizes of molecules between the domain was first defined as a domain of shared ho- nucleoplasm and cytoplasm, which act as gatekeep- mology between Sad1 in Schizosaccharomyces pombe ers of the nucleus (Fig. 1a). and UNC-84 in Caenorhabditis elegans. An amino- Compared with the cytoplasm, the role of nuclear terminal nucleoplasmic domain of SUN proteins in- mechanotransduction in gene regulation is much teracts with nuclear lamina and chromatin-binding less well understood. The cytoskeleton is the major proteins. In contrast, a carboxyl-terminal region, cellular determinant of the physical and mechani- containing a conserved SUN domain, protrudes into cal properties, which mediates cellular responses to various environmental cues from the surroundings. the PNS. The direct interactions of SUN proteins Cytoskeletal polymers, including actin filaments, and KASH proteins across the NE provide a core microtubules and intermediate filaments, can con- link between the nucleoskeleton and the cytoskele- ton. Thus, it is reasonable to assume that the LINC nect to the NE through linkers of nucleoskeleton Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 936 Natl Sci Rev, 2018, Vol. 5, No. 6 REVIEW complex mediates mechanically induced signals tecture. The research on nuclear lamins has focused along the NE and then into the nucleus. on their regulation of nuclear architecture. New evi- The human genome contains six genes encoding dence shows that A-type lamins and their associated KASH proteins. Four of them are nuclear envelope NE proteins are key regulators of mechanotrans- spectrin-repeat proteins (nesprins1–4) . Com- duction. Han et al. reported that low SS suppresses pared with nesprin 4, nesprins 1–3 are widely dis- the level of lamin A in ECs, and this suppression tributed and predominantly mediate mechanotrans- subsequently leads to EC dysfunction . Down- duction to the nucleus in most cells. Cells exposed regulation of A-type lamins in ECs facilitates T cell to a mechanical stimulus show altered cell signal- migration through EC layers, suggesting that the ing and cytoskeletal organization leading to changes regulation of EC nuclear stiffness by lamin A/C may in the cellular phenotype. The nucleus is also force- modulate subendothelial migration of blood-borne responsive, and these mechano responses not only immune cells, a key process of atherosclerosis . affect nuclear functions, but also subnuclear struc- Brosig et al. showed that expression of dominant tures and changes in subnuclear movement . negative mutants of nesprin and SUN enhances The functions of nesprins have been demonstrated in the transcriptional activity of NFκB in C2C12 cellular responses to mechanical force systems. For cells, suggesting that the degradation of nuclear instance, nesprin1 knockdown increases the number LINC complexes causes conformational changes in of focal adhesions and substrate traction while de- chromatin structure and organization that modulate creasing EC migration in response to cyclic strain, transcription factor binding or transcriptional resulting in abnormal adhesion and migration . processes . In response to pathological cyclic The physical link from the cytoskeleton to NE is stretch, lamin A/C expression is depressed, which decisive for mechanotransduction. The disruption ultimately increases the proliferation of vascular of nesprin–SUN complexes disrupts force transmis- smooth muscle cells (VSMCs) . In addition, sion from the cytoskeleton to the nucleus, which lamin A is also involved in sensing forces generated perturbs the mechanical control of cell differentia- from cells within tissue during differentiation. tion and abrogates their stretch-induced prolifera- Matrix stiffness directly influences the lamin A tion . A recent study by Han et al. showed that level, and lamin A transcription is modulated by the nesprin 2 is sensitive to the SS and regulates EC func- vitamin A/retinoic acid (RA) pathway with broad tions. Under low SS, the repressed nesprin 2 is cor- roles in development . Lamin A in human cell related with increased proliferation and apoptosis of lines from tumor cells to primary mesenchymal stem ECs  (Fig. 1b). cells (MSCs) also contributes to migration . SUN proteins are single-pass transmembrane Emerin is another ubiquitous integral membrane proteins localized in the INM. Both human and protein that is localized in the INM and associates mouse genomes encode at least six SUN proteins. with nesprin 1, 2, SUN1/2, and lamin A/C. Loss of While SUN1 and SUN2 are widely expressed, SUN3 emerin brings about Emery–Dreifuss muscular dys- and SPAG4 appear to be limited in several tissue trophy (EDMD), characterized by muscle weaken- types . SUN proteins can also interact with ing, and potentially lethal cardiac conduction system lamin B to mediate nuclear migration . SUN1 defects. Emerin has a LEM-domain and therefore ablation weakens the nucleoskeleton, leading to re- binds to barrier-to-autointegration factor (BAF), a duced force transmission to the nucleus . Trans- conserved chromatin protein that is essential for mission electron microscope (TEM) analysis has cell division. BAF conscribes emerin to chromatin revealed that nesprin 2 or lamin A knockdown re- and regulates high-order chromatin structure dur- sults in degradation of the NE phospholipid bilayer, ing nuclear assembly. Most studies on emerin focus suggesting that nesprin 2 and lamin A regulate NE on skeletal muscle and myocardium, while little re- stability and nuclear structure . Furthermore, search has been conducted on VSMCs. Recent re- the organization of nuclei is disrupted in SUN 1/2 sults indicate that emerin and lamin A/C bind to the double-knockout mice. respective sequencing-specific motifs of transcrip- The nuclear lamina, containing A-type lamins tion factors to modulate the hyperstretch-induced (lamins A and C, encoded by the LMNA gene) and dysfunction of VSMCs  (Fig. 1c). Combined B-type lamins (lamins B1 and B2, encoded by the with these results, it has been suggested that ne- LMNB1 and LMNB2 genes), is linked to chromatin sprin 2, lamin A/C, and emerin modulate the pro- and participates in gene transcription. B-type lamins liferation of ECs and VSMCs in arterial walls in are broadly expressed. In contrast, A-type lamins, response to cyclic strain and SS associated with hy- which are expressed in all differentiated cell types, pertension. Other studies have shown that MRTF- participate in gene expression, cell signaling, high- A, a cardiomyocyte-related mechanically sensitive order chromatin organization, and nuclear archi- transcription factor, plays an important role in Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 REVIEW Han et al. 937 cardiac development. The reduction in lamin A/C , and SS regulates the migration, apoptosis, and emerin reduces the viability of the nucleus and proliferation and gene expressions of VSMCs in cytoskeletal microfilaments and results in a decrease an EC-dependent manner [79–81]. SS modulates in the activity of the transcription factor MRTF-A the EC phenotype, with subsequent alterations and suppression of its translocation . This re- in the release of pro-inflammatory cytokines, as sult also shows that lamin A/C and emerin-induced well as VSMC proliferation, apoptosis and gene changes in the nuclear structure can directly affect expressions [82,83]. gene regulation. On the other hand, nuclear skele- With the use of a systemic biological approach ton elements can also interact directly with chromo- encompassing high-throughput screening, bioinfor- somes or multiple transcriptional regulators. For ex- matics analysis and biological validation, a vascular ample, lamin A/C binds to pRb, c-Fos and ERK1/2 cell mechanotransduction network has been estab- , whereas emerin interacts with β-catenin, BAF lished . Using proteomic analysis, the protein and GCL . These results suggest that the struc- profiles of rat aorta cultured under low shear stress ture of the nucleus, plasticity, and mechanical trans- (LSS, 5 dyn/cm ) and normal shear stress (NSS, mission between the nucleus and the skeleton play 15 dyn/cm ) were compared (Fig. 2a). The differ- important roles in the intracellular signal transduc- ential expressed proteins were analyzed by Inge- tion pathways. nuity Pathway Analysis (https://analysis.ingenuity. In recent years, several new processes associated com/pa/installer/select). A signaling network that with nuclear membrane remodeling have been re- is highly associated with mechanotransduction ex- ported, including NE repair after rupture and NE erted by LSS, involving platelet-derived growth fac- autophagy. Despite major progress made in nuclear tor BB (PDGF-BB), transforming growth factor mechanotransduction sensors, many other ques- beta1 (TGFβ1), lamin A, lysyl oxidase (LOX), tions remain to be studied, such as whether the and extracellular signal-regulated kinases 1/2 (ERK DNA binding of NE proteins modulated by mechan- 1/2), was revealed (Fig. 2b). The network mediating ical forces is direct or other complexes are involved, LSS-induced migration and proliferation of ECs and whether LINC complex defects could be mainly at- VSMCs and the cross-talk between these two cell tributed to changes in the pre-stress state of the types was investigated in a co-cultured system in a cell and how various NE proteins interact with each parallel-plate flow chamber (Fig. 2c). In comparison other. The network of mechanotransduction in the to NSS, LSS upregulates migration and proliferation nucleus and the NE proteins involved require further of ECs and VSMCs, and increases the production study. of PDGF-BB and TGFβ1. Additionally, PDGF-BB recombinant protein shows an effect similar to LSS on ECs and VSMCs. In contrast, TGFβ1recombi- MECHANOTRANSDUCTION NETWORK nant protein has a similar effect on ECs to PDGF-BB, BASED ON HIGH-THROUGHPUT but not on VSMCs. When PDGF-BB expression is BIOTECHNOLOGY ‘knocked down’ in ECs, the effects of LSS are mit- Mechanotransduction initiates the cascade reaction igated or abolished, and this effect is also blocked process through a complicated signaling network in by pre-incubation of VSMCs with PDGF-BB neu- cells. High-throughput biotechnology, such as pro- tralized antibody. TGFβ1 ‘knockdown’ in ECs and teomics, phosphoproteomics, genomics, and tran- neutralizing antibody pre-incubation with VSMCs scriptomics, among others, can provide enormous mitigates the EC responses to LSS but has no ef- amount of data for bioinformatics and/or system fect on VSMCs. These results suggest that ECs re- biology analyses to reveal key genes or proteins in spond to LSS stimuli by upregulating PDGF-BB and the regulatory network. These key hubs and bridging TGFβ1. However, these two growth factors play nodes of the network can enable the prioritization different roles in LSS-induced vascular remodeling. of potential targets for subsequent validation exper- While PDGF-BB is involved in the paracrine control between ECs and VSMCs, TGFβ1 takes part in the iments for clinical translation [56,76,77]. feedback control from VSMCs to ECs . ECs and VSMCs are the major cellular con- Over at least the last two decades, molecular and stituents of the vessel wall. The interactions, cell biology approaches have been used to research crosstalk and synergy between VSMCs and ECs the roles and involvement of multiple molecules in play a critical role in vascular biology in health mechanotransduction. Most, if not all, of these stud- and disease. ECs in the intima of the arterial wall are exposed to SS constantly, and then transduce ies focus on the level of the single molecule and/or the mechanical stimuli to intracellular signals pathway. To date, information regarding mechan- [6,10]. ECs induce gene expressions of PDGF-AA, otransduction in cardiovascular cells at the sys- PDGF-BB and TGFβ in co-cultured VSMCs temic level is largely lacking, resulting in difficulties Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 938 Natl Sci Rev, 2018, Vol. 5, No. 6 REVIEW Figure 2. Schematic drawing outlining the vascular cell mechanotransduction network based on mechano-vascular proteomics. (a) 2D electrophoresis 2 2 (2DE) gels of aorta cultured under different shear stresses. The protein profiles of rat aorta cultured under NSS (15 dyn/cm ) and LSS (5 dyn/cm ) are compared by using comparative proteomic techniques, 2DE and MALDI-TOF mass spectrometry. (b) IPA reveals a potential mechanotransduction network. Differentially expressed proteins are analyzed by IPA and a signaling network that is highly correlated with mechanotransduction of LSS, involving PDGF-BB, TGFβ1, lamin A, LOX and ERK 1/2. (c) Validation of the network by the parallel-plate flow chamber (left panel) for the co-culture model of ECs and VSMCs in vivo. In the EC/VSMC co-culture parallel-plate flow chamber, ECs and VSMCs are grown on opposite sides of a 10- μm-thick polyethylene terephthalate (PET) membrane, and the ECs are subjected to SS. The interactions of ECs and VSMCs are able to occur through 0.4-μm diameter PET membrane pores. Using this system, the expressions of molecules involved in the networks, namely, PDGF-BB, TGFβ1, lamin A, LOX and phospho-ERK1/2, and the migration and proliferation of ECs and VSMCs separately under two levels of shear stress at 5 and 15 dyn/cm are studied. networked approaches for a wide variety of biomedi- elucidating the complex regulatory mechanisms of cells in response to stresses in a comprehensive cal research. It is expected that such high-throughput manner. Recent advancement in high-throughput technology will also be used in the near future to technology, such as ‘omics’ experiments, have fa- explore life phenomena, reveal the pathogenesis of cilitated comprehensive, systematic, dynamic and diseases and search for drug targets. Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 REVIEW Han et al. 939 Although based on the concept of proteomics stress regulates the expression of candidate lncRNAs and networks, scholars have conducted a large in ECs, which in turn regulates downstream met- amount of research investigating vascular tissue/cell alloprotease AMZ2 expression via lncRNA bind- regulatory mechanisms during vascular remodeling, ing to the repressive chromatin mark H3K27me3 which is involved in a variety of proteins and a . Yao and colleagues found that 68 lncRNAs and very complex and dynamic regular network, but the 255 mRNAs are up-modulated in the aorta of spon- available research still does not describe the cell taneously hypertensive rats, whereas 167 lncRNAs mechanotransduction network synthetically. Re- and 272 mRNAs are downregulated . Moreover, search examining modification-related proteomics 15% cyclic strain increases lncRNA XR007793 ex- after translation is in its infancy. Dynamic and quan- pression. XR007793 knockdown attenuates VSMC titative analysis of the full spectrum and large-scale, proliferation and migration and inhibits signal trans- high-flux studies examining protein modification af- ducers and activators of transcription 2 (stat2), LIM ter translation remains a problem that must be domain only 2 (lmo2) and interferon regulatory fac- solved in the future. Furthermore, the verification tor 7 (irf7) . lncRNA n342419, termed MAN- and functional analysis of mechanotransduction in TIS, is downregulated in patients with idiopathic the context of vascular biology as well as the intracel- pulmonary arterial hypertension (IPAH), whereas it lular mechanical stress signal transduction network is upregulated in the carotid arteries of Macaca fascic- established by existing data are far from complete. ularis subjected to an atherosclerosis regression diet A more efficient and accurate new theory, algorithm as well as in ECs isolated from glioblastoma patients and software based on high-throughput technolog- . Given the variety of epigenetic mechanisms ical data remain to be established. Research on the regulated by lncRNA, it is anticipated that lncRNA above issues seems likely to be an important frontier regulation of vascular remodeling in response to me- in the study of vascular mechanobiology. chanical stimuli will generate fruitful results. Mechanoregulation of miRNAs in MECHANOREGULATION OF NON-CODING vascular remodeling RNAS IN VASCULAR REMODELING miRNAs are endogenous, non-coding and single- Non-coding RNAs (ncRNAs) are functional RNAs stranded RNAs of 18–22 nucleotides that consti- that are not translated into proteins. This new class of tute a novel class of gene regulators . miRNAs RNAs is functionally involved in the epigenetic reg- bind to the 3 -untranslated regions (3 -UTRs) of ulations of gene expression, and ncRNAs are ubiq- their target mRNAs, leading to direct degradation of uitously present in animals and plants as well as mRNA or translational repression by a perfect com- fungi [84,85]. Increasing evidence has revealed that plement in plant cells or imperfect complement in ncRNAs participate in the regulation of various bi- animal cells . The roles of miRNAs in vascu- ological processes, e.g., metabolism, development, lar development and diseases have been studied in- cell differentiation, proliferation and apoptosis, cell, tensively [95,96]. As the changes of cell phenotype, oncogenesis, and vascular homeostasis [84–87]. migration, proliferation, hypertrophy and apoptosis, Non-coding RNAs include microRNAs (miR- among others, are major events involved in vascular NAs), long non-coding RNAs (long ncRNAs, lncR- remodeling, very many miRNAs have been shown to NAs), small interfering RNAs (siRNAs), piwi- regulate these events in the context of mechanoreg- interacting RNAs (piRNAs), and small nucleolar ulation. In the following sections, we review recent RNAs (snoRNAs) [85,88]. Littleisknown about findings related to miRNAs in mechanobiology with the roles of siRNAs, piRNAs and snoRNAs in the an emphasis on shear stress effects on ECs and me- cardiovascular system, let alone their engagement in chanical stretch effects on VSMCs. mechanotransduction, which may provide new re- search opportunities. lncRNAs are defined as non-protein-coding tran- Shear stress scripts longer than 200 nucleotides . At least sev- Shear stress (SS) exertion on ECs plays significant eral thousand lncRNAs likely exist in the mammalian roles in regulating vascular homeostasis and patho- genome. It appears that only one-fifth of transcrip- physiology [6,7]. Laminar SS regulates the expres- tion across the human genome is involved in protein- sion of miR-126, vascular cell adhesion molecule coding genes, showing at least four times more lncR- 1 (VCAM-1), and syndecan-4 (SDC-4) in ECs NAs than protein-coding RNAs . As epigenetic . miR-126 is increased during long-term expo- regulation mechanisms of lncRNAs have gained am- sure to flow and shows a crosstalk between ECs ple attention in research, new efforts show that shear and VSMCs in response to SS, which is mediated Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 940 Natl Sci Rev, 2018, Vol. 5, No. 6 REVIEW The expression of miR-126–5p is increased in through miR-126 [97,98]. Co-culture of VSMCs atheroprone areas in a KLF2-dependent manner. with ECs or treatment of VSMCs with conditioned medium from static EC monoculture (EC-CM) in- The inhibition of miR-126–5p, but not miR-126–3p, creases miR-126 level in VSMCs with concomitant recapitulates the effects of pri-miR-126a knockout, suppression of FOXO3, BCL2 and IRS1 mRNAs which increases the area of the atherosclerosis lesion, and VSMC turnover. These effects are abolished by promotes macrophage infiltration, and decreases en- either inhibition of endothelial miR-126 or the ap- dothelial repair in mice . On the other hand, plication of laminar SS to ECs. Consistently, deple- miR-10a is drastically decreased in the disturbed tion of miR-126 in mice inhibits neointimal forma- flow area under arterial tress, when compared to tion of carotid arteries resulting from cessation of the laminar flow area. The NF- κB pathway is acti- blood flow [ 98]. vated and NF-κB target genes are upregulated when In response to laminar SS, miR-23b is induced miR-10a is inhibited in ECs in vitro , show- by the transcription factor Kruppel-like ¨ factor 2 ing that the absence of miR-10a in the disturbed (KLF2) [99,100]. Laminar SS also results in the flow area causes ECs to be susceptible to inflamma- expression of miR-19a, which directly targets cy- tion . Interestingly, miR-10a exhibits the low- clin D1, leading to cell cycle arrest at G1/S tran- est expression level among all the examined shear- sition. Thus, miR-19a would be a key regulator responsive miRs in ECs under oscillatory SS . In terms of the regulatory mechanism, miR-10a ex- of cell cycle progression in response to laminar pression is regulated by KLF2 through modulation SS . SS induces expression of miR-30 fam- of RAR α–RARE binding, with consequent regula- ily members in a KLF2-dependent manner . tion of GATA6/VCAM-1 in ECs . All these re- miR-101 expression is also significantly upregulated sults indicate that miR-10a is downregulated in ECs in human umbilical vein ECs (HUVECs) exposed by disturbed flow via KLF2. to laminar SS at 12 dyn/cm . miR-101 targets a Atheroprone SS induces the expression of miR- mammalian target of rapamycin (mTOR), which in turn causes cell cycle arrest at the G1/S transi- 92a in concert with oxidized LDL treatment (ox- tion and thus suppresses EC proliferation . Co- LDL) in HUVECs [113–116]. As miR-92a targets culturing ECs with VSMCs under static conditions the 3 -UTR of KLF2 mRNA, atheroprotective lam- causes initial increases in miR-146a, -708, -451, and inar flow downregulates miR-92a to induce KLF2 -98 in ECs. SS (12 dyn/cm ) applied to co-cultured . Interestingly, blockade of miR-92a expres- −/− ECs for 24 h augments the expression of these sion in Ldlr mice restores endothelial function four anti-inflammatory miRNAs [ 104]. These four and decreases atherosclerosis . The expression anti-inflammatory miRNAs are highly expressed in of miR-34 is upregulated by both p53 and oscil- neointimal ECs in injured arteries under physiolog- latory SS . Blockade of endogenous miR-34a ical flow rather than flow stagnation. Decreased ex- decreases the expression of VCAM-1 and intercel- pression of miR-146a can accelerate neointima for- lular adhesion molecule-1 (ICAM-1) in ECs. Con- mation of injured rat carotid artery under physio- versely, miR-34a overexpression increases the level logical flow while overexpression in miR-146a in- of VCAM-1 and ICAM-1, which promotes mono- hibits neointima formation in the rat or mouse cyte adhesion to ECs . Furthermore, laminar . SS increases miR-34a expression levels in human umbilical cord blood-derived endothelial progeni- Under disturbed flow, the expression of tor cells (EPCs). An inverse correlation of miR-34a miR-21 is induced in HUVECs [105,106]. Os- and Foxj2 expressions is involved in the endothe- cillatory SS induces AP-1-dependent miR-21 lial differentiation of EPCs [ 119]. These results indi- expression, which directly targets peroxisome cate that miR-34a is a mechanosensitive miRNA that proliferator-activated receptor α (PPARα)mRNA, may have distinct functions in ECs versus EPCs. In thereby increasing the expression of VCAM1 and addition to the abovementioned miRNAs, there is a C-C motif chemokine 2/monocyte chemoattractant protein 1 (CCL2/MCP1) to promote adhesion panel of SS-sensitive miRNAs that regulate various of monocytes to ECs. Oscillatory SS induction aspects of endothelial biology. of miR-21 is a positive feedback loop that in- creases the pro-inflammatory responses of vascular endothelium . Oscillatory SS also induces Cyclic stretch miR-663 expression in cultured HUVECs . VSMCs in a vascular medium are loaded with The disturbed flow also induces the expression of cyclic circumferential strain, i.e., cyclic stretch. Song miR-712, which promotes endothelial inflammation et al. reported that an elevated stretch (16% elonga- and increases endothelial permeability, resulting in tion, 1 Hz) increases miR-21 expression in cultured a pro-atherogenic phenotype . human aortic smooth muscle cells (HASMCs), Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 REVIEW Han et al. 941 tial downstream targets of BMP3, are all increased whereas a moderate stretch (10% elongation, 1 Hz) in the grafted veins. While miR-33 mimics attenuate, decreases expression. Because miR-21 is involved in HASMC proliferation, the complex of miR-21 and miR-33 inhibitors accelerate VSMC proliferation. programmed cell death protein 4 (PDCD4) regu- Moreover, recombinant BMP3 increases VSMC lates stretch-induced apoptosis . Cyclic stretch proliferation and phospho-smad2 and -smad5 also modulates the VSMC phenotype through sev- levels. By contrast, BMP3 siRNAs have the opposite eral other miRNAs. In VSMCs of the portal vein, effect [ 125]. To explore the mechanism on a cellular the stretch-induced mRNA expression of contrac- molecular level, venous VSMCs were exposed to tile markers is reduced in the absence of miR- mimic arterial cyclic stretch by a cell stretch loading 143/145 . In stretched portal veins and in system in vitro. The arterial stretch shows an increase pressurized carotid arteries, the expression of miR- in proliferation and repression of miR-33 expres- 144/451 is downregulated, which is inversely cor- sion. Additionally, BMP3 expression and smad2 related with the expression and phosphorylation of and smad5 phosphorylation are enhanced (Fig. 3b). AMPK . In human aortic VSMCs cultured on Perivascular multi-point injection of agomiR-33 in collagen I, 16% stretch suppresses miR-145 expres- the graft vein rat model in vivo not only attenuates sion in connection with reduced expression of con- BMP3 expression as well as smad2 and smad5 phos- tractile markers of VSMCs. miR-145 overexpression phorylation, but also clearly accelerates neointimal formation and cell proliferation in the grafted veins can partially recover the expression of these mark- (Fig. 3c). These effects of agomiR-33 on grafted ers in the stretched cells. Furthermore, the stretch- veins can be reversed by local injection of BMP3 activated extracellular signal-regulated kinase 1/2 lentivirus . (ERK1/2) and upregulated angiotensin-converting Although the work by Huang et al. demonstrates enzyme (ACE) account for the inhibition of miR- that miR-33 affects vein graft-induced neointimal 145 expression . VSMCs exposed to physi- hyperplasia, a number of important questions re- ological waveforms differentiate further compared with those under static or sinusoidal cyclic strain. main unanswered, including the molecular mecha- Increased expression of miR-143, -145, and VSMC nism and mechanosensors that control miR-33 ex- markers desmin, calponin and SM-22 are found in pression in response to arterial stretch of VSMCs these more differentiated cells. Uniform dynamic and vascular injury. Whether miR-33 is involved in stretch not only increases the expression level of human vein graft adaptation would be another in- miR-143 and -145, but also increases that of miR- teresting research topic. Interestingly, the human 221 . genome encodes two miR-33 isoforms, namely, Once a vein graft is transplanted into the arterial miR-33a and miR-33b, which are, respectively, co- system, such as a saphenous vein in a coronary artery expressed with SREBP2 and SREBP1 . Thus, bypass graft, the transplanted vessels are exposed additional studies using human samples or animal to the arterial mechanical environment. Arterialized models such as non-human primates that express cyclic stretch will affect VSMC functions in the miR-33a and miR-33b will be important to trans- grafted veins, including excessive proliferation and late these findings to the intimal hyperplasia ob- migration, which causes neointima formation and served in human vein grafts [ 126]. The mecha- ultimately leads to vein graft failure. Huang et al. nism of miRNAs in mechanotransduction has not been fully elucidated. Specifically, miRNA can reg- reported a novel mechanism by which miR-33 me- ulate multiple target genes in the cell signaling diates mechanical stretch-induced venous VSMC network, greatly influencing biological pathways, proliferation and neointimal hyperplasia. Thus, miR- cell functions and the dynamic balance of the ves- 33 targeting might be a novel therapeutic strategy to sel wall. miRNA as a biomarker or therapeutic prevent vein graft failure and neointimal hyperplasia target will be superior to the existing biomark- . Embedded in the intronic sequences of genes ers or treatment drugs for cardiovascular disease encoding sterol regulatory element-binding proteins (SREBPs), miR-33 has been shown to modulate [130–133]. the proliferation of several cell types in vivo and in Therapies based on ncRNAs represent one of vitro [126–128]. Huang et al. first reported that in new frontier in human disease treatment. There are a graft vein rat model, neointimal hyperplasia and still many unknown areas in the research of ncR- cell proliferation is significantly increased (Fig. 3a). NAs under mechanotransduction. Multiple tran- Furthermore, miR-33 expression is decreased one, scriptional factors/co-activators/co-suppressors in- two and four weeks post-grafting [ 125]. In contrast, volved in the regulation of miRNA expression the expression of bone morphogenetic protein 3 under mechanical regulation need to be eluci- (BMP3), a putative target of miR-33, and the phos- dated. The unknown area is not only a chal- phorylation of smad2 and smad5, which are poten- lenge but also an opportunity, and scientists and Downloaded from https://academic.oup.com/nsr/article/5/6/933/4775140 by DeepDyve user on 13 July 2022 942 Natl Sci Rev, 2018, Vol. 5, No. 6 REVIEW Figure 3. Schematic outlining the mechanobiological study of the roles of miRNAs and their target gene for exploring biomarkers. (a) Pathological outcomes in an animal model in vivo. Neointimal hyperplasia and cell proliferation are increased significantly, and miR-33 expression is decreased in rat vein grafts one, two and four weeks post-surgery. (b) Exploration of the biomechanical mechanism at the cellular and molecular levels in vitro.Use of a cyclic strain loading model of venous VSMCs and computation prediction of the miRNA target gene. The arterial stretch increases venous VSMC proliferation, represses miR-33 expression, and enhances target gene, BMP3, expression and phosphorylation of its downstream molecules smad2 and smad5, which are involved in VSMC proliferation. (c) Verifying the discovery in the animal model in vivo. The perivascular multi-point injection in the graft vein rat model demonstrates that agomiR-33 not only attenuates BMP3 expression and smad2 and smad5 phosphorylation, but also attenuates neointimal formation and cell proliferation in grafted veins. clinicians need to work together to overcome the improved understanding of mechanobiology in vas- difficulties. cular remodeling may facilitate the development of novel therapeutic approaches targeting vascular im- pairments. The potential targets include, but are not SUMMARY AND PERSPECTIVES limited to, mechanosensors, key proteins, miRNAs Vascular remodeling is a common pathophysiologi- and lncRNAs in ECs and VSMCs. Thus, identifica- cal process in cardiovascular diseases and mechano- tion of these key molecules would be a priority in stimuli, including SS and cyclic strain, which are subsequent investigations for clinical translation. critically important factors regulating vascular phys- The core concept of the ‘stress-growth’ the- iology and pathology. Vascular cells, mainly ECs ory is the interplay and synergism between the and VSMCs, can sense the various forms of me- mechanical micro-environment and chemical chanical signals, transform them into intracellular micro-environment within cells. The results from biochemical signals i.e., mechanotransduction, and mechanobiology studies, including mechanical, then initiate cascades of cellular responses that ulti- biochemical, cellular and molecular mechanisms, mately regulate vascular functions (Fig. 4). Vascular will provide valuable information revealing the mechanobiology elucidates the molecular and cellu- major mechanical and chemical factors in the lar basis of responses in ECs and VSMCs under me- organism. The mechanobiological study should include the following: experimental approaches chanical conditions. With the advancement of high- throughput technologies, gene-editing methods and using animal models (or clinical data) in vivo; computational biology, there are new and exciting mechanistic studies at the cellular and molecular research opportunities in the area of mechanobi- level in vitro; validation using gene manipulation ology for researchers from different disciplines. 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National Science Review – Oxford University Press
Published: Nov 1, 2018
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