Flowing blood generates a frictional force called shear stress that has major effects on vascular function. Branches and bends of arteries are exposed to complex blood flow patterns that exert low or low oscillatory shear stress, a mechanical environment that promotes vascular dysfunction and atherosclerosis. Conversely, physiologically high shear stress is protective. Endothelial cells are critical sensors of shear stress but the mechanisms by which they decode complex shear stress environments to regulate physiological and pathophysiological responses remain incompletely understood. Several laboratories have advanced this field by integrating specialized shear-stress models with systems biology approaches, including transcriptome, methylome and proteome profiling and functional screening platforms, for unbiased identification of novel mechanosensitive signalling pathways in arteries. In this Review, we describe these studies, which reveal that shear stress regulates diverse processes and demonstrate that multiple pathways classically known to be involved in embryonic development, such as BMP–TGFβ, WNT, Notch, HIF1α, TWIST1 and HOX family genes, are regulated by shear stress in arteries in adults. We propose that mechanical activation of these pathways evolved to orchestrate vascular development but also drives atherosclerosis in low shear stress regions of adult arteries.
Shear stress regulates atherosclerosis by altering endothelial cell physiology.
Systems biology approaches have identified multiple shear stress-regulated pathways in the endothelium, including several pathways classically known to be involved in embryogenesis.
Blood flow-mediated regulation of developmental pathways orchestrates valve formation and angiogenesis to optimize tissue perfusion.
By contrast, in arteries in adults, these blood flow-regulated pathways lead to inflammation, vascular dysfunction and atherosclerosis.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kwak, B. R. et al. Biomechanical factors in atherosclerosis: mechanisms and clinical implications. Eur. Heart J. 35, 3013–3020 (2014).
Cheng, C. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113, 2744–2753 (2006).
Sorescu, G. P. et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ. Res. 95, 773–779 (2004).
Passerini, A. G. et al. Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta. Proc. Natl Acad. Sci. USA 101, 2482–2487 (2004).
Dai, G. et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc. Natl Acad. Sci. USA 101, 14871–14876 (2004).
Iiyama, K. et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ. Res. 85, 199–207 (1999).
Cuhlmann, S. et al. Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-kappa B regulation that promotes arterial inflammation. Circ. Res. 108, 950–959 (2011).
Zakkar, M. et al. Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis. Circ. Res. 103, 726–732 (2008).
Zakkar, M. et al. Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state. Arterioscler. Thromb. Vasc. Biol. 29, 1851–1857 (2009).
Mahmoud, M. M. et al. TWIST1 integrates endothelial responses to flow in vascular dysfunction and atherosclerosis. Circ. Res. 119, 450–462 (2016).
Caplan, B. A. & Schwartz, C. J. Increased endothelial cell turnover in areas of in-vivo Evans Blue uptake in pig aorta. Atherosclerosis 17, 401–417 (1973).
Davies, P. F., Remuzzi, A., Gordon, E. J., Dewey, C. F. & Gimbrone, M. A. Turbulent fluid shear-stress induces vascular endothelial-cell turnover invitro. Proc. Natl Acad. Sci. USA 83, 2114–2117 (1986).
Zeng, L. F. et al. Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. Proc. Natl Acad. Sci. USA 106, 8326–8331 (2009).
Cancel, L. M. & Tarbell, J. M. The role of mitosis in LDL transport through cultured endothelial cell monolayers. Am. J. Physiol. Heart Circ. Physiol. 300, H769–H776 (2011).
Chaudhury, H. et al. c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis. Arterioscler. Thromb. Vasc. Biol. 30, 546–553 (2010).
Pedrigi, R. M. et al. Influence of shear stress magnitude and direction on atherosclerotic plaque composition. R. Soc. Open Sci. 3, 160588 (2016).
Nam, D. et al. Partial carotid ligation is a model of acutely induced disturbed flow, leading to rapid endothelial dysfunction and atherosclerosis. Am. J. Physiol. Heart Circ. Physiol. 297, H1535–H1543 (2009).
Dunn, J. et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J. Clin. Invest. 124, 3187–3199 (2014).
Mitra, R. et al. The comparative effects of high fat diet or disturbed blood flow on glycocalyx integrity and vascular inflammation. Transl Med. Commun. 3, 10 (2018).
Stone, P. H. et al. Prediction of progression of coronary artery disease and clinical outcomes using vascular profiling of endothelial shear stress and arterial plaque characteristics: the PREDICTION study. Circulation 126, 172–181 (2012).
Samady, H. et al. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 124, 779–788 (2011).
Gijsen, F., van der Giessen, A., van der Steen, A. & Wentzel, J. Shear stress and advanced atherosclerosis in human coronary arteries. J. Biomech. 46, 240–247 (2013).
Timmins, L. H. et al. Oscillatory wall shear stress is a dominant flow characteristic affecting lesion progression patterns and plaque vulnerability in patients with coronary artery disease. J. R. Soc. Interface 14, https://doi.org/10.1098/rsif.2016.0972 (2017).
Chatzizisis, Y. S. et al. Prediction of the localization of high-risk coronary atherosclerotic plaques on the basis of low endothelial shear stress - an intravascular ultrasound and histopathology natural history study. Circulation 117, 993–1002 (2008).
Koskinas, K. C. et al. Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress. Arterioscler. Thromb. Vasc. Biol. 33, 1494–1504 (2013).
Pedrigi, R. M. et al. Inducing persistent flow disturbances accelerates atherogenesis and promotes thin cap fibroatheroma development in D374Y-PCSK9 hypercholesterolemic minipigs. Circulation 132, 1003–1012 (2015).
White, S. J. et al. Characterization of the differential response of endothelial cells exposed to normal and elevated laminar shear stress. J. Cell. Physiol. 226, 2841–2848 (2011).
Bryan, M. T. et al. Mechanoresponsive networks controlling vascular inflammation. Arterioscler. Thromb. Vasc. Biol. 34, 2199–2205 (2014).
Feng, S. et al. Mechanical activation of hypoxia-inducible factor 1alpha drives endothelial dysfunction at atheroprone sites. Arterioscler. Thromb. Vasc. Biol. https://doi.org/10.1161/atvbaha.117.309249 (2017).
Wu, D. et al. HIF-1alpha is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. eLife 6, https://doi.org/10.7554/eLife.25217 (2017).
Cheng, C. et al. Shear stress affects the intracellular distribution of eNOS: direct demonstration by a novel in vivo technique. Blood 106, 3691–3698 (2005).
Fledderus, J. O. et al. Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2. Blood 109, 4249–4257 (2007).
Yamawaki, H., Pan, S., Lee, R. T. & Berk, B. C. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J. Clin. Invest. 115, 733–738 (2005).
Fang, Y., Shi, C., Manduchi, E., Civelek, M. & Davies, P. F. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc. Natl Acad. Sci. USA 107, 13450–13455 (2010).
Guo, D., Chien, S. & Shyy, J. Y. Regulation of endothelial cell cycle by laminar versus oscillatory flow - distinct modes of interactions of AMP-activated protein kinase and Akt pathways. Circ. Res. 100, 564–571 (2007).
Ajami, N. E. et al. Systems biology analysis of longitudinal functional response of endothelial cells to shear stress. Proc. Natl Acad. Sci. USA 114, 10990–10995 (2017).
Zeng, L. F., Zhang, Y. K., Chien, S., Liu, X. & Shyy, J. Y. J. The role of p53 deacetylation in p21(Waf1) regulation by laminar flow. J. Biol. Chem. 278, 24594–24599 (2003).
Frueh, J. et al. Systems biology of the functional and dysfunctional endothelium. Cardiovasc. Res. 99, 334–341 (2013).
Simmons, R. D., Kumar, S., Thabet, S. R., Sur, S. & Jo, H. Omics-based approaches to understand mechanosensitive endothelial biology and atherosclerosis. Wiley Interdiscip. Rev. Syst. Biol. Med. 8, 378–401 (2016).
Jiang, Y. Z., Manduchi, E., Jimenez, J. M. & Davies, P. F. Endothelial epigenetics in biomechanical stress: disturbed flow-mediated epigenomic plasticity in vivo and in vitro. Arterioscler Thromb Vasc Biol 35, 1317–1326 (2015).
Firasat, S., Hecker, M., Binder, L. & Asif, A. R. Advances in endothelial shear stress proteomics. Expert Rev. Proteomics 11, 611–619 (2014).
Kumar, S., Kim, C. W., Simmons, R. D. & Jo, H. Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis: mechanosensitive athero-miRs. Arterioscler. Thromb. Vasc. Biol. 34, 2206–2216 (2014).
Ni, C.-W. et al. Discovery of novel mechanosensitive genes in vivo using mouse carotid artery endothelium exposed to disturbed flow. Blood 116, E66–E73 (2010).
Chen, B. P. et al. DNA microarray analysis of gene expression in endothelial cells in response to 24-h shear stress. Physiol. Genomics 7, 55–63 (2001).
Serbanovic-Canic, J. et al. Zebrafish model for functional screening of flow-responsive genes. Arterioscler. Thromb. Vasc. Biol. 37, 130–143 (2017).
Bjorck, H. M. et al. Characterization of shear-sensitive genes in the normal rat aorta identifies Hand2 as a major flow-responsive transcription factor. PLoS ONE 7, e52227 (2012).
Garcia-Cardena, G., Comander, J., Anderson, K. R., Blackman, B. R. & Gimbrone, M. A. Jr. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc. Natl Acad. Sci. USA 98, 4478–4485 (2001).
Holliday, C. J., Ankeny, R. F., Jo, H. & Nerem, R. M. Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 301, H856–867 (2011).
Butcher, J. T. et al. Transcriptional profiles of valvular and vascular endothelial cells reveal phenotypic differences: influence of shear stress. Arterioscler. Thromb. Vasc. Biol. 26, 69–77 (2006).
Civelek, M., Manduchi, E., Riley, R. J., Stoeckert, C. J. & Davies, P. F. Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ. Res. 105, 453–461 (2009).
Civelek, M., Manduchi, E., Riley, R. J., Stoeckert, C. J., Jr. & Davies, P. F. Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis. Circ. Cardiovasc. Genet. 4, 243–252 (2011).
Jiang, Y. Z., Manduchi, E., Stoeckert, C. J., Jr. & Davies, P. F. Arterial endothelial methylome: differential DNA methylation in athero-susceptible disturbed flow regions in vivo. BMC Genomics 16, 506 (2015).
Bondareva, O. et al. Identification of atheroprone shear stress responsive regulatory elements in endothelial cells. Cardiovasc. Res. https://doi.org/10.1093/cvr/cvz027 (2019).
Wang, X. L., Fu, A., Raghavakaimal, S. & Lee, H. C. Proteomic analysis of vascular endothelial cells in response to laminar shear stress. Proteomics 7, 588–596 (2007).
Wang, X. L., Fu, A., Spiro, C. & Lee, H. C. Proteomic analysis of vascular endothelial cells-effects of laminar shear stress and high glucose. J. Proteomics Bioinform. 2, 445–454 (2009).
Burghoff, S. & Schrader, J. Secretome of human endothelial cells under shear stress. J. Proteome Res. 10, 1160–1169 (2011).
Sun, X. et al. Activation of integrin alpha5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells. Proc. Natl Acad. Sci. USA 113, 769–774 (2016).
Maleszewska, M., Vanchin, B., Harmsen, M. C. & Krenning, G. The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence. Angiogenesis 19, 9–24 (2016).
White, M. P. et al. NOTCH1 regulates matrix gla protein and calcification gene networks in human valve endothelium. J. Mol. Cell Cardiol. 84, 13–23 (2015).
Qiao, C. et al. Deep transcriptomic profiling reveals the similarity between endothelial cells cultured under static and oscillatory shear stress conditions. Physiol. Genomics 48, 660–666 (2016).
Kumar, S. et al. Functional screening of mammalian mechanosensitive genes using Drosophila RNAi library- Smarcd3/Bap60 is a mechanosensitive pro-inflammatory gene. Sci. Rep. 6, 36461 (2016).
Xu, J. et al. GPR68 senses flow and is essential for vascular physiology. Cell 173, 762–775 e716 (2018).
Dunn, J. et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J. Clin. Invest. 124, 3187–3199 (2014).
Maimari, N., Pedrigi, R. M., Russo, A., Broda, K. & Krams, R. Integration of flow studies for robust selection of mechanoresponsive genes. Thromb. Haemost. 115, 474–483 (2016).
Hitzel, J. et al. Oxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells. Nat. Commun. 9, 2292 (2018).
Sorescu, G. P. et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J. Biol. Chem. 278, 31128–31135 (2003).
Chang, K. et al. Bone morphogenic protein antagonists are coexpressed with bone morphogenic protein 4 in endothelial cells exposed to unstable flow in vitro in mouse aortas and in human coronary arteries: role of bone morphogenic protein antagonists in inflammation and atherosclerosis. Circulation 116, 1258–1266 (2007).
Zhou, J. et al. Force-specific activation of Smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow. Proc. Natl Acad. Sci. USA 109, 7770–7775 (2012).
Baeyens, N. et al. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J. Cell Biol. 214, 807–816 (2016).
Jin, Y. et al. Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nat. Cell Biol. 19, 639–652 (2017).
Vion, A. C. et al. Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. J. Cell Biol. 217, 1651–1665 (2018).
Corti, P. et al. Interaction between alk1 and blood flow in the development of arteriovenous malformations. Development 138, 1573–1582 (2011).
Laux, D. W. et al. Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence. Development 140, 3403–3412 (2013).
Rochon, E. R., Menon, P. G. & Roman, B. L. Alk1 controls arterial endothelial cell migration in lumenized vessels. Development 143, 2593–2602 (2016).
Mitrofan, C. G. et al. Bone morphogenetic protein 9 (BMP9) and BMP10 enhance tumor necrosis factor-alpha-induced monocyte recruitment to the vascular endothelium mainly via activin receptor-like kinase 2. J. Biol. Chem. 292, 13714–13726 (2017).
Zhou, J. et al. BMP receptor-integrin interaction mediates responses of vascular endothelial Smad1/5 and proliferation to disturbed flow. J. Thromb. Haemost. 11, 741–755 (2013).
Kim, C. W. et al. Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 33, 1350–1359 (2013).
Yao, Y. et al. Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circ. Res. 107, 485–494 (2010).
Derwall, M. et al. Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 613–622 (2012).
Anderson, K. P., Kern, C. B., Crable, S. C. & Lingrel, J. B. Isolation of a gene encoding a functional zinc finger protein homologous to erythroid Kruppel-like factor: identification of a new multigene family. Mol. Cell. Biol. 15, 5957–5965 (1995).
Dekker, R. J. et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100, 1689–1698 (2002).
Senbanerjee, S. et al. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J. Exp. Med. 199, 1305–1315 (2004).
Lin, Z. et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ. Res. 96, e48–e57 (2005).
Groenendijk, B. C., Hierck, B. P., Gittenberger-De Groot, A. C. & Poelmann, R. E. Development-related changes in the expression of shear stress responsive genes KLF-2, ET-1, and NOS-3 in the developing cardiovascular system of chicken embryos. Dev. Dyn. 230, 57–68 (2004).
Groenendijk, B. C. et al. Changes in shear stress-related gene expression after experimentally altered venous return in the chicken embryo. Circ. Res. 96, 1291–1298 (2005).
Lee, J. S. et al. KIf2 is an essential regulator of vascular hemodynamic forces in vivo. Dev. Cell 11, 845–857 (2006).
Kuo, C. T. et al. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes Dev. 11, 2996–3006 (1997).
Esmerats, J. F. et al. Disturbed flow increases UBE2C (ubiquitin E2 ligase C) via loss of miR-483-3p, inducing aortic valve calcification by the HIF-1alpha (hypoxia-inducible factor-1alpha) pathway in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 39, 467-481, (2019).
Evans, P. C. et al. A novel type of deubiquitinating enzyme. J. Biol. Chem. 278, 23180–23186 (2003).
Akhtar, S. et al. Endothelial hypoxia-inducible factor-1 alpha promotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a. Hypertension 66, 1220–1226 (2015).
de Vries, M. R. & Quax, P. H. Plaque angiogenesis and its relation to inflammation and atherosclerotic plaque destabilization. Curr. Opin. Lipidol. 27, 499–506 (2016).
Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).
Lawson, N. D. et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675–3683 (2001).
You, L. R. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005).
Mack, J. J. & Iruela-Arispe, M. L. NOTCH regulation of the endothelial cell phenotype. Curr. Opin. Hematol. 25, 212–218 (2018).
Timmerman, L. A. et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev. 18, 99–115 (2004).
Robert-Moreno, A., Espinosa, L., de la Pompa, J. L. & Bigas, A. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development 132, 1117–1126 (2005).
Qin, W. D. et al. Notch1 inhibition reduces low shear stress-induced plaque formation. Int. J. Biochem. Cell Biol. 72, 63–72 (2016).
Jahnsen, E. D. et al. Notch1 is pan-endothelial at the onset of flow and regulated by flow. PLOS ONE 10, e0122622 (2015).
Mack, J. J. et al. NOTCH1 is a mechanosensor in adult arteries. Nat. Commun. 8, 1620 (2017).
Fang, J. S. et al. Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nat. Commun. 8, 2149 (2017).
Polacheck, W. J. et al. A non-canonical Notch complex regulates adherens junctions and vascular barrier function. Nature 552, 258–262 (2017).
Watson, O. et al. Blood flow suppresses vascular Notch signalling via dll4 and is required for angiogenesis in response to hypoxic signalling. Cardiovasc. Res. 100, 252–261 (2013).
Neto, F. et al. YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development. eLife 7, e31037 (2018).
Wang, L. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016).
Wang, K. C. et al. Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc. Natl Acad. Sci. USA 113, 11525–11530 (2016).
Xu, S., Koroleva, M., Yin, M. & Jin, Z. G. Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells. Transl Res. 176, 18–28.e2 (2016).
Li, B. et al. c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow. J. Clin. Invest. 129, 1167–1179 (2019).
Gelfand, B. D. et al. Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression. Arterioscler. Thromb. Vasc. Biol. 31, 1625–1633 (2011).
Li, R. et al. Shear stress-activated wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos. Arterioscler. Thromb. Vasc. Biol. 34, 2268–2275 (2014).
Biswas, P. et al. PECAM-1 affects GSK-3beta-mediated beta-catenin phosphorylation and degradation. Am. J. Pathol. 169, 314–324 (2006).
Pearson, J. C., Lemons, D. & McGinnis, W. Modulating Hox gene functions during animal body patterning. Nat. Rev. Genet. 6, 893–904 (2005).
Rinn, J. L., Bondre, C., Gladstone, H. B., Brown, P. O. & Chang, H. Y. Anatomic demarcation by positional variation in fibroblast gene expression programs. PLOS Genet. 2, e119 (2006).
Cooley, B. C. et al. TGF-beta signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci. Transl Med. 6, 227ra34, (2014).
Chen, P. Y. et al. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J. Clin. Invest. 125, 4514–4528 (2015).
Gonzalez, D. M. & Medici, D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signal. 7, re8, (2014).
Camenisch, T. D. et al. Temporal and distinct TGF beta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev. Biol. 248, 170–181 (2002).
Maddaluno, L. et al. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498, 492–496 (2013).
Ranchoux, B. et al. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131, 1006–1018 (2015).
Moonen, J.-R. A. J. et al. Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress. Cardiovasc. Res. 108, 377–386 (2015).
Evrard, S. M. et al. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat. Commun. 7, 11853, (2016).
Mahmoud, M. M. et al. Shear stress induces endothelial-to-mesenchymal transition via the transcription factor Snail. Sci. Rep. 7, 3375, (2017).
Welch-Reardon, K. M., Wu, N. & Hughes, C. C. W. A role for partial endothelial-mesenchymal transitions in angiogenesis? Arterioscler. Thromb. Vasc. Biol. 35, 303–308 (2015).
Kinsella, M. G. & Fitzharris, T. P. Origin of cushion tissue in the developing chick heart: cinematographic recordings of in situ formation. Science 207, 1359–1360 (1980).
Thisse, B., Elmessal, M. & Perrinschmitt, F. The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res. 15, 3439–3453 (1987).
Gitelman, I. Twist protein in mouse embryogenesis. Dev. Biol. 189, 205–214 (1997).
el Ghouzzi, V. et al. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat. Genet. 15, 42–46 (1997).
Howard, T. D. et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet. 15, 36–41 (1997).
Chakraborty, S. et al. Twist1 promotes heart valve cell proliferation and extracellular matrix gene expression during development in vivo and is expressed in human diseased aortic valves. Dev. Biol. 347, 167–179 (2010).
Rodrigues, C. O., Nerlick, S. T., White, E. L., Cleveland, J. L. & King, M. L. A Myc-Slug (Snail2)/Twist regulatory circuit directs vascular development. Development 135, 1903–1911 (2008).
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Chen, H. F. et al. Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat. Commun. 5, 4697 (2014).
Zhao, Z., Rahman, M. A., Chen, Z. G. & Shin, D. M. Multiple biological functions of Twist1 in various cancers. Oncotarget 8, 20380–20393 (2017).
Mammoto, T., Jiang, A., Jiang, E. & Mammoto, A. Role of Twist1 phosphorylation in angiogenesis and pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 55, 633–644 (2016).
Li, J. et al. Endothelial TWIST1 promotes pathological ocular angiogenesis. Invest. Ophthalmol. Visual Sci. 55, 8267–8277 (2014).
Dichgans, M. et al. Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke 45, 24–36 (2014).
Nelson, C. P. et al. Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nat. Genet. 49, 1385–1391 (2017).
Nikpay, M. et al. A comprehensive 1000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet. 47, 1121–1130 (2015).
van der Harst, P. & Verweij, N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ. Res. 122, 433–443 (2018).
Malik, R. et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat. Genet. 50, 524–537 (2018).
Rosand, J. et al. Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol. 15, 174–184 (2016).
Traylor, M. et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol. 11, 951–962 (2012).
Chapman, W. B. The effect of the heart-beat upon the development of the vascular system in the chick. Am. J. Anat. 23, 175–203 (1918).
Tanaka, M., Chen, Z., Bartunkova, S., Yamasaki, N. & Izumo, S. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126, 1269–1280 (1999).
May, S. R., Stewart, N. J., Chang, W. & Peterson, A. S. A Titin mutation defines roles for circulation in endothelial morphogenesis. Dev. Biol. 270, 31–46 (2004).
Lucitti, J. L. et al. Vascular remodeling of the mouse yolk sac requires hemodynamic force. Development 134, 3317–3326 (2007).
Chouinard-Pelletier, G., Jahnsen, E. D. & Jones, E. A. Increased shear stress inhibits angiogenesis in veins and not arteries during vascular development. Angiogenesis 16, 71–83 (2013).
Song, J. W. & Munn, L. L. Fluid forces control endothelial sprouting. Proc. Natl Acad. Sci. USA 108, 15342–15347 (2011).
Nicoli, S. et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 464, 1196–1200 (2010).
Bussmann, J., Wolfe, S. A. & Siekmann, A. F. Arterial-venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling. Development 138, 1717–1726 (2011).
Packham, I. M. et al. Microarray profiling reveals CXCR4a is downregulated by blood flow in vivo and mediates collateral formation in zebrafish embryos. Physiol. Genomics 38, 319–327 (2009).
Lenard, A. et al. Endothelial cell self-fusion during vascular pruning. PLoS Biol. 13, e1002126 (2015).
Djonov, V., Schmid, M., Tschanz, S. A. & Burri, P. H. Intussusceptive angiogenesis: its role in embryonic vascular network formation. Circ. Res. 86, 286–292 (2000).
Baeyens, N., Bandyopadhyay, C., Coon, B. G., Yun, S. & Schwartz, M. A. Endothelial fluid shear stress sensing in vascular health and disease. J. Clin. Invest. 126, 821–828 (2016).
Diaz, M. F. et al. Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J. Exp. Med. 212, 665–680 (2015).
Chen, X., Gays, D., Milia, C. & Santoro, M. M. Cilia control vascular mural cell recruitment in vertebrates. Cell Rep. 18, 1033–1047 (2017).
Sakabe, M. et al. YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proc. Natl Acad. Sci. USA 114, 10918–10923 (2017).
Nakajima, H. et al. Flow-dependent endothelial YAP regulation contributes to vessel maintenance. Dev. Cell 40, 523–536.e6 (2017).
Franco, C. A. et al. Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling. elife 5, e07727 (2016).
Chen, Q. et al. Haemodynamics-driven developmental pruning of brain vasculature in zebrafish. PLOS Biol. 10, e1001374 (2012).
Kochhan, E. et al. Blood flow changes coincide with cellular rearrangements during blood vessel pruning in zebrafish embryos. PlOS ONE 8, e75060 (2013).
Udan, R. S., Vadakkan, T. J. & Dickinson, M. E. Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sac. Development 140, 4041–4050 (2013).
Franco, C. A. et al. Dynamic endothelial cell rearrangements drive developmental vessel regression. PLOS Biol. 13, e1002125 (2015).
Meeson, A., Palmer, M., Calfon, M. & Lang, R. A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis. Development 122, 3929–3938 (1996).
Meeson, A. P., Argilla, M., Ko, K., Witte, L. & Lang, R. A. VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development 126, 1407–1415 (1999).
Yashiro, K., Shiratori, H. & Hamada, H. Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch. Nature 450, 285–288 (2007).
Tricot, O. et al. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation 101, 2450–2453 (2000).
Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).
le Noble, F. et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development 131, 361–375 (2004).
Buschmann, I. et al. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development 137, 2187–2196 (2010).
Hwa, J. J. et al. Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow. Sci. Rep. 7, 11965 (2017).
Chong, D. C., Koo, Y., Xu, K., Fu, S. & Cleaver, O. Stepwise arteriovenous fate acquisition during mammalian vasculogenesis. Dev. Dyn. 240, 2153–2165 (2011).
North, T. E. et al. Hematopoietic stem cell development is dependent on blood flow. Cell 137, 736–748 (2009).
Wang, L. et al. A blood flow-dependent klf2a-NO signaling cascade is required for stabilization of hematopoietic stem cell programming in zebrafish embryos. Blood 118, 4102–4110 (2011).
Isogai, S., Lawson, N. D., Torrealday, S., Horiguchi, M. & Weinstein, B. M. Angiogenic network formation in the developing vertebrate trunk. Development 130, 5281–5290 (2003).
Adamo, L. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009).
Heckel, E. et al. Oscillatory flow modulates mechanosensitive klf2a expression through trpv4 and trpp2 during heart valve development. Curr. Biol. 25, 1354–1361 (2015).
Hove, J. R. et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421, 172–177 (2003).
Shelton, E. L. & Yutzey, K. E. Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development. Dev. Biol. 317, 282–295 (2008).
The authors are funded by the British Heart Foundation, Medical Research Council and the National Centre for the Replacement, Refinement and Reduction of Animals in Research.
The authors declare no competing interests.
Peer review information
Nature Reviews Cardiology thanks P. F. Davies, H. Jo, P. H. Stone and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- DNA methylome
A set of DNA methylation modifications that vary between cell types and according to physiological context.
- Endothelial-to-mesenchymal transition
A process of endothelial cell plasticity that leads to a mesenchymal state.
- Differentially methylated regions
Regions of the genome that exhibit differences in DNA methylation status across different biological samples.
- Reduced-representation bisulfite sequencing
Method for mapping whole-genome DNA methylation that is based on sequencing CpG-rich regions and involves methylation-sensitive conversion of cytosines to uracils (methylcytosines are not converted) with the use of sodium bisulfate followed by next-generation sequencing.
About this article
Cite this article
Souilhol, C., Serbanovic-Canic, J., Fragiadaki, M. et al. Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nat Rev Cardiol 17, 52–63 (2020). https://doi.org/10.1038/s41569-019-0239-5
Biomechanics and Modeling in Mechanobiology (2021)
BMC Cardiovascular Disorders (2020)
Nature Reviews Cardiology (2020)
Laminar flow inhibits the Hippo/YAP pathway via autophagy and SIRT1-mediated deacetylation against atherosclerosis
Cell Death & Disease (2020)
Nature Reviews Cardiology (2020)