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  • Review Article
  • Published:

Flow-induced reprogramming of endothelial cells in atherosclerosis

Nature Reviews Cardiology volume 20, pages 738–753 (2023)Cite this article

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Abstract

Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthy phenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.

Key points

  • Atherosclerosis preferentially develops in curved and branching regions of arteries, which are sites of disturbed blood flow and low-magnitude oscillatory shear stress.

  • Disturbed flow delivers low-magnitude oscillatory shear stress to endothelial cells, which causes endothelial cells to adopt pro-atherogenic functions and gene transcription programmes.

  • Endothelial cells detect shear stress magnitudes and patterns through mechanosensory proteins and organelles and transmit these signals into intracellular changes via mechanotransduction pathways.

  • Advances in omics approaches and experimental models have helped to identify numerous novel potential therapeutic targets for atherosclerosis.

  • Disturbed-flow-induced reprogramming of endothelial cells (which we term FIRE) promotes endothelial inflammation, endothelial-to-mesenchymal transition and endothelial-to-immune-cell-like transition during atherogenesis.

  • Genes, proteins and pathways involved in FIRE are promising targets for anti-atherogenic therapies.

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Fig. 1: Atherosclerosis preferentially develops at sites of disturbed flow.
Fig. 2: Models of atherosclerosis induced by disturbed flow.
Fig. 3: Mechanosensors and mechanosignal transduction pathways in endothelial cells.
Fig. 4: Single-cell RNA sequencing reveals disturbed-flow-induced reprogramming of endothelial cells.

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References

  1. Libby, P., Ridker, P. M. & Maseri, A. Inflammation and atherosclerosis. Circulation 105, 1135–1143 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Herrington, W., Lacey, B., Sherliker, P., Armitage, J. & Lewington, S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ. Res. 118, 535–546 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Davignon, J. & Ganz, P. Role of endothelial dysfunction in atherosclerosis. Circulation 109, III27–III32 (2004).

    Article  PubMed  Google Scholar 

  4. Bennett, M. R., Sinha, S. & Owens, G. K. Vascular smooth muscle cells in atherosclerosis. Circ. Res. 118, 692–702 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Libby, P. The changing landscape of atherosclerosis. Nature 592, 524–533 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Libby, P., Ridker, P. M., Hansson, G. K. & Atherothrombosis, L. T. N. O. Inflammation in atherosclerosis: from pathophysiology to practice. J. Am. Coll. Cardiol. 54, 2129–2138 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Caro, C. G., Fitz-Gerald, J. M. & Schroter, R. C. Arterial wall shear and distribution of early atheroma in man. Nature 223, 1159–1160 (1969).

    Article  CAS  PubMed  Google Scholar 

  8. VanderLaan, P. A., Reardon, C. A. & Getz, G. S. Site specificity of atherosclerosis: site-selective responses to atherosclerotic modulators. Arterioscler Thromb. Vasc. Biol. 24, 12–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Tarbell, J. M. Mass transport in arteries and the localization of atherosclerosis. Annu. Rev. Biomed. Eng. 5, 79–118 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Fang, Y., Wu, D. & Birukov, K. G. Mechanosensing and mechanoregulation of endothelial cell functions. Compr. Physiol. 9, 873–904 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Gallego-Colon, E., Daum, A. & Yosefy, C. Statins and PCSK9 inhibitors: a new lipid-lowering therapy. Eur. J. Pharmacol. 878, 173114 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  13. Kwak, B. R. et al. Biomechanical factors in atherosclerosis: mechanisms and clinical implications. Eur. Heart J. 35, 3013–3020 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tarbell, J. M., Shi, Z. D., Dunn, J. & Jo, H. Fluid mechanics, arterial disease, and gene expression. Annu. Rev. Fluid Mech. 46, 591–614 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Andueza, A. et al. Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study. Cell Rep. 33, 108491 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chiu, J. J. & Chien, S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol. Rev. 91, 327–387 (2011).

    Article  PubMed  Google Scholar 

  17. Simmons, R. D., Kumar, S. & Jo, H. The role of endothelial mechanosensitive genes in atherosclerosis and omics approaches. Arch. Biochem. Biophys. 591, 111–131 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Fernandez-Friera, L. et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (progression of early subclinical atherosclerosis) study. Circulation 131, 2104–2113 (2015).

    Article  PubMed  Google Scholar 

  19. Laclaustra, M. et al. Femoral and carotid subclinical atherosclerosis association with risk factors and coronary calcium: the AWHS study. J. Am. Coll. Cardiol. 67, 1263–1274 (2016).

    Article  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng, C. et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation 113, 2744–2753 (2006).

    Article  PubMed  Google Scholar 

  22. Kumar, S., Kang, D. W., Rezvan, A. & Jo, H. Accelerated atherosclerosis development in C57Bl6 mice by overexpressing AAV-mediated PCSK9 and partial carotid ligation. Lab. Invest. 97, 935–945 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim, C. W. et al. Disturbed flow promotes arterial stiffening through thrombospondin-1. Circulation 136, 1217–1232 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kuhlmann, M. T. et al. Implantation of a carotid cuff for triggering shear-stress induced atherosclerosis in mice. J. Vis. Exp. https://doi.org/10.3791/3308 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tang, D., Geng, F., Yu, C. & Zhang, R. Recent application of zebrafish models in atherosclerosis research. Front. Cell Dev. Biol. 9, 643697 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Schlegel, A. Zebrafish models for dyslipidemia and atherosclerosis research. Front. Endocrinol. 7, 159 (2016).

    Article  Google Scholar 

  27. Baek, K. I. et al. Vascular injury in the zebrafish tail modulates blood flow and peak wall shear stress to restore embryonic circular network. Front. Cardiovasc. Med. 9, 841101 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hsu, J. J. et al. Contractile and hemodynamic forces coordinate Notch1b-mediated outflow tract valve formation. JCI Insight 4, e124460 (2019).

    Article  PubMed Central  Google Scholar 

  29. Lee, J. et al. 4-Dimensional light-modulation of cardiac trabeculation. J. Clin. Investig. 126, 1679–1690 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lee, J. et al. Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation. JCI Insight https://doi.org/10.1172/jci.insight.96672 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Baek, K. I. et al. Flow-responsive vascular endothelial growth factor receptor-protein kinase C isoform epsilon signaling mediates glycolytic metabolites for vascular repair. Antioxid. Redox Signal. 28, 31–43 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dewey, C. F. Jr., Bussolari, S. R., Gimbrone, M. A. Jr. & Davies, P. F. The dynamic response of vascular endothelial cells to fluid shear stress. J. Biomech. Eng. 103, 177–185 (1981).

    Article  PubMed  Google Scholar 

  33. Lawrence, M. B., McIntire, L. V. & Eskin, S. G. Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion. Blood 70, 1284–1290 (1987).

    Article  CAS  PubMed  Google Scholar 

  34. Rezvan, A., Ni, C.-W., Alberts-Grill, N. & Jo, H. Animal, in vitro, and ex vivo models of flow-dependent atherosclerosis: role of oxidative stress. Antioxid. Redox Signal. 15, 1433–1448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Colgan, O. C. et al. Regulation of bovine brain microvascular endothelial tight junction assembly and barrier function by laminar shear stress. Am. J. Physiol. Heart Circ. Physiol. 292, H3190–H3197 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Orsenigo, F. et al. Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat. Commun. 3, 1208 (2012).

    Article  PubMed  Google Scholar 

  37. Caolo, V. et al. Shear stress and VE-cadherin. Arterioscler. Thromb. Vasc. Biol. 38, 2174–2183 (2018).

    Article  CAS  PubMed  Google Scholar 

  38. Levesque, M. J., Nerem, R. M. & Sprague, E. A. Vascular endothelial cell proliferation in culture and the influence of flow. Biomaterials 11, 702–707 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Lin, K. et al. Molecular mechanism of endothelial growth arrest by laminar shear stress. Proc. Natl Acad. Sci. USA 97, 9385–9389 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dimmeler, S., Haendeler, J., Rippmann, V., Nehls, M. & Zeiher, A. M. Shear stress inhibits apoptosis of human endothelial cells. FEBS Lett. 399, 71–74 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Dimmeler, S., Assmus, B., Hermann, C., Haendeler, J. & Zeiher, A. M. Fluid shear stress stimulates phosphorylation of Akt in human endothelial cells: involvement in suppression of apoptosis. Circ. Res. 83, 334–341 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, J. et al. Shear stress regulates endothelial cell autophagy via redox regulation and Sirt1 expression. Cell Death Dis. 6, e1827 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Warboys, C. M. et al. Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler. Thromb. Vasc. Biol. 34, 985–995 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Doddaballapur, A. et al. Laminar shear stress inhibits endothelial cell metabolism via KLF2-mediated repression of PFKFB3. Arterioscler. Thromb. Vasc. Biol. 35, 137–145 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Yamamoto, K., Imamura, H. & Ando, J. Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+ signaling in vascular endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 315, H1477–H1485 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Go, Y. M. et al. Disturbed flow induces systemic changes in metabolites in mouse plasma: a metabolomics study using ApoE−/− mice with partial carotid ligation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R62–R72 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Hong, S. G. et al. Flow pattern-dependent mitochondrial dynamics regulates the metabolic profile and inflammatory state of endothelial cells. JCI Insight https://doi.org/10.1172/jci.insight.159286 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Heo, K.-S., Fujiwara, K. & Abe, J.-I. Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Circ. J. 75, 2722–2730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hwang, J. et al. Pulsatile versus oscillatory shear stress regulates NADPH oxidase subunit expression: implication for native LDL oxidation. Circ. Res. 93, 1225–1232 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hwang, J. et al. Oscillatory shear stress stimulates endothelial production of O2− from p47phox-dependent NAD(P)H oxidases, leading to monocyte adhesion. J. Biol. Chem. 278, 47291–47298 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Jo, H., Song, H. & Mowbray, A. Role of NADPH oxidases in disturbed flow- and BMP4- induced inflammation and atherosclerosis. Antioxid. Redox Signal. 8, 1609–1619 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Zhang, J. X. et al. Low shear stress induces vascular eNOS uncoupling via autophagy-mediated eNOS phosphorylation. Biochim. Biophys. Acta Mol. Cell. Res. 1865, 709–720 (2018).

    Article  CAS  PubMed  Google Scholar 

  53. Chachisvilis, M., Zhang, Y. L. & Frangos, J. A. G protein-coupled receptors sense fluid shear stress in endothelial cells. Proc. Natl Acad. Sci. USA 103, 15463–15468 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Li, L. et al. GTP cyclohydrolase I phosphorylation and interaction with GTP cyclohydrolase feedback regulatory protein provide novel regulation of endothelial tetrahydrobiopterin and nitric oxide. Circ. Res. 106, 328–336 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. McNally, J. S. et al. Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress. Am. J. Physiol. Heart Circ. Physiol. 285, H2290–H2297 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Meyer, J. W. & Schmitt, M. E. A central role for the endothelial NADPH oxidase in atherosclerosis. FEBS Lett. 472, 1–4 (2000).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. Nagel, T., Resnick, N., Dewey, C. F. Jr. & Gimbrone, M. A. Jr. Vascular endothelial cells respond to spatial gradients in fluid shear stress by enhanced activation of transcription factors. Arterioscler. Thromb. Vasc. Biol. 19, 1825–1834 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Sterpetti, A. V. et al. Shear stress increases the release of interleukin-1 and interleukin-6 by aortic endothelial cells. Surgery 114, 911–914 (1993).

    CAS  PubMed  Google Scholar 

  60. Souilhol, C., Harmsen, M. C., Evans, P. C. & Krenning, G. Endothelial–mesenchymal transition in atherosclerosis. Cardiovasc. Res. 114, 565–577 (2018).

    Article  CAS  PubMed  Google Scholar 

  61. Tardy, Y., Resnick, N., Nagel, T., Gimbrone, M. A. Jr. & Dewey, C. F. Jr. Shear stress gradients remodel endothelial monolayers in vitro via a cell proliferation-migration-loss cycle. Arterioscler. Thromb. Vasc. Biol. 17, 3102–3106 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Tressel, S. L. et al. Angiopoietin-2 stimulates blood flow recovery after femoral artery occlusion by inducing inflammation and arteriogenesis. Arterioscler. Thromb. Vasc. Biol. 28, 1989–1995 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tressel, S. L., Huang, R. P., Tomsen, N. & Jo, H. Laminar shear inhibits tubule formation and migration of endothelial cells by an angiopoietin-2 dependent mechanism. Arterioscler. Thromb. Vasc. Biol. 27, 2150–2156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Nerem, R. M., Levesque, M. J. & Cornhill, J. F. Vascular endothelial morphology as an indicator of the pattern of blood flow. J. Biomech. Eng. 103, 172–176 (1981).

    Article  CAS  PubMed  Google Scholar 

  65. Flaherty, J. T. et al. Endothelial nuclear patterns in the canine arterial tree with particular reference to hemodynamic events. Circ. Res. 30, 23–33 (1972).

    Article  CAS  PubMed  Google Scholar 

  66. Langille, B. L. & Adamson, S. L. Relationship between blood flow direction and endothelial cell orientation at arterial branch sites in rabbits and mice. Circ. Res. 48, 481–488 (1981).

    Article  CAS  PubMed  Google Scholar 

  67. Franke, R. P. et al. Induction of human vascular endothelial stress fibres by fluid shear stress. Nature 307, 648–649 (1984).

    Article  CAS  PubMed  Google Scholar 

  68. Kim, D. W., Langille, B. L., Wong, M. K. & Gotlieb, A. I. Patterns of endothelial microfilament distribution in the rabbit aorta in situ. Circ. Res. 64, 21–31 (1989).

    Article  CAS  PubMed  Google Scholar 

  69. Tzima, E. et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426–431 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Steward, R. Jr., Tambe, D., Hardin, C. C., Krishnan, R. & Fredberg, J. J. Fluid shear, intercellular stress, and endothelial cell alignment. Am. J. Physiol. Cell Physiol. 308, C657–C664 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Coan, D. E., Wechezak, A. R., Viggers, R. F. & Sauvage, L. R. Effect of shear stress upon localization of the Golgi apparatus and microtubule organizing center in isolated cultured endothelial cells. J. Cell Sci. 104, 1145–1153 (1993).

    Article  PubMed  Google Scholar 

  72. Kwon, H. B. et al. In vivo modulation of endothelial polarization by Apelin receptor signalling. Nat. Commun. 7, 11805 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Demos, C., Tamargo, I. & Jo, H. Biomechanical regulation of endothelial function in atherosclerosis. Biomech. Coron. Atheroscler. Plaque 4, 3–47 (2021).

    Article  Google Scholar 

  74. Albarrán-Juárez, J. et al. Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation. J. Exp. Med. 215, 2655–2672 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Bartosch, A. M. W., Mathews, R. & Tarbell, J. M. Endothelial glycocalyx-mediated nitric oxide production in response to selective AFM pulling. Biophys. J. 113, 101–108 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Caolo, V. et al. Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells. eLife https://doi.org/10.7554/eLife.50684 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Chuntharpursat-Bon, E. et al. PIEZO1 and PECAM1 interact at cell–cell junctions and partner in endothelial force sensing. Commun. Biol. 6, 358 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dela Paz, N. G. & Frangos, J. A. Rapid flow-induced activation of Gαq/11 is independent of Piezo1 activation. Am. J. Physiol. Cell Physiol. 316, C741–c752 (2019).

    Article  Google Scholar 

  79. Florian, J. A. et al. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ. Res. 93, e136–e142 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Li, J. et al. Piezo1 integration of vascular architecture with physiological force. Nature 515, 279–282 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mack, J. J. et al. NOTCH1 is a mechanosensor in adult arteries. Nat. Commun. 8, 1620 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Mehta, V. et al. The guidance receptor plexin D1 is a mechanosensor in endothelial cells. Nature 578, 290–295 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nauli, S. M. et al. Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1. Circulation 117, 1161–1171 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shin, H. et al. Fine control of endothelial VEGFR-2 activation: caveolae as fluid shear stress shelters for membrane receptors. Biomech. Model Mechanobiol. 18, 5–16 (2019).

    Article  CAS  PubMed  Google Scholar 

  85. Wang, S. et al. Endothelial cation channel PIEZO1 controls blood pressure by mediating flow-induced ATP release. J. Clin. Invest. 126, 4527–4536 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Yamamoto, K., Korenaga, R., Kamiya, A. & Ando, J. Fluid shear stress activates Ca2+ influx into human endothelial cells via P2X4 purinoceptors. Circ. Res. 87, 385–391 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Zheng, Q. et al. Mechanosensitive channel PIEZO1 senses shear force to induce KLF2/4 expression via CaMKII/MEKK3/ERK5 axis in endothelial cells. Cells https://doi.org/10.3390/cells11142191 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Ridone, P., Vassalli, M. & Martinac, B. Piezo1 mechanosensitive channels: what are they and why are they important. Biophys. Rev. 11, 795–805 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ranade, S. S. et al. Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc. Natl Acad. Sci. USA 111, 10347–10352 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Xu, J. et al. GPR68 senses flow and is essential for vascular physiology. Cell 173, 762–775.e16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tzima, E., del Pozo, M. A., Shattil, S. J., Chien, S. & Schwartz, M. A. Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J. 20, 4639–4647 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, C. et al. Coupling of integrin α5 to annexin A2 by flow drives endothelial activation. Circ. Res. 127, 1074–1090 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Schwarz, U. S. & Gardel, M. L. United we stand: integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction. J. Cell Sci. 125, 3051–3060 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Mohan, S., Mohan, N. & Sprague, E. A. Differential activation of NF-kappa B in human aortic endothelial cells conditioned to specific flow environments. Am. J. Physiol. 273, C572–C578 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Murthy, S. E., Dubin, A. E. & Patapoutian, A. Piezos thrive under pressure: mechanically activated ion channels in health and disease. Nat. Rev. Mol. Cell Biol. 18, 771–783 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Wang, S. et al. P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction. J. Clin. Invest. 125, 3077–3086 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Iring, A. et al. Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. J. Clin. Invest. 129, 2775–2791 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Harry, B. L. et al. Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 28, 2003–2008 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tzima, E. Role of small GTPases in endothelial cytoskeletal dynamics and the shear stress response. Circ. Res. 98, 176–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Wang, L. et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540, 579–582 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Civelekoglu-Scholey, G. et al. Model of coupled transient changes of Rac, Rho, adhesions and stress fibers alignment in endothelial cells responding to shear stress. J. Theor. Biol. 232, 569–585 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Tzima, E., Kiosses, W. B., del Pozo, M. A. & Schwartz, M. A. Localized cdc42 activation, detected using a novel assay, mediates microtubule organizing center positioning in endothelial cells in response to fluid shear stress. J. Biol. Chem. 278, 31020–31023 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Palazzo, A. F. et al. Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536–1541 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Orr, A. W. et al. The subendothelial extracellular matrix modulates NF-κB activation by flow: a potential role in atherosclerosis. J. Cell Biol. 169, 191–202 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chen, J. et al. αvβ3 Integrins mediate flow-induced NF-κB activation, proinflammatory gene expression, and early atherogenic inflammation. Am. J. Pathol. 185, 2575–2589 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stupack, D. G. & Cheresh, D. A. ECM remodeling regulates angiogenesis: endothelial integrins look for new ligands. Sci. STKE 2002, pe7 (2002).

    Article  PubMed  Google Scholar 

  107. Li, B. et al. c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow. J. Clin. Invest. 129, 1167–1179 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Dekker, R. J. et al. Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am. J. Pathol. 167, 609–618 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lin, Z. et al. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ. Res. 96, e48–e57 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. van Thienen, J. V. et al. Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization. Cardiovasc. Res. 72, 231–240 (2006).

    Article  PubMed  Google Scholar 

  111. Young, A. et al. Flow activation of AMP-activated protein kinase in vascular endothelium leads to Kruppel-like factor 2 expression. Arterioscler. Thromb. Vasc. Biol. 29, 1902–1908 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu, C. et al. Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces. Circ. Res. 117, e41–e53 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. SenBanerjee, S. et al. KLF2 is a novel transcriptional regulator of endothelial proinflammatory activation. J. Exp. Med. 199, 1305–1315 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hsieh, C. Y. et al. Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells. J. Biomed. Sci. 16, 12 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Fledderus, J. O. et al. KLF2 primes the antioxidant transcription factor Nrf2 for activation in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 28, 1339–1346 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Berk, B. C. Atheroprotective signaling mechanisms activated by steady laminar flow in endothelial cells. Circulation 117, 1082–1089 (2008).

    Article  PubMed  Google Scholar 

  117. Abe, J. & Berk, B. C. Novel mechanisms of endothelial mechanotransduction. Arterioscler. Thromb. Vasc. Biol. 34, 2378–2386 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kasler, H. G., Victoria, J., Duramad, O. & Winoto, A. ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol. Cell Biol. 20, 8382–8389 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sohn, S. J., Li, D., Lee, L. K. & Winoto, A. Transcriptional regulation of tissue-specific genes by the ERK5 mitogen-activated protein kinase. Mol. Cell Biol. 25, 8553–8566 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Woo, C. H. et al. ERK5 activation inhibits inflammatory responses via peroxisome proliferator-activated receptor δ (PPARδ) stimulation. J. Biol. Chem. 281, 32164–32174 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Akaike, M. et al. The hinge–helix 1 region of peroxisome proliferator-activated receptor γ1 (PPARγ1) mediates interaction with extracellular signal-regulated kinase 5 and PPARγ1 transcriptional activation: involvement in flow-induced PPARγ activation in endothelial cells. Mol. Cell Biol. 24, 8691–8704 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Woo, C. H. et al. Extracellular signal-regulated kinase 5 SUMOylation antagonizes shear stress-induced antiinflammatory response and endothelial nitric oxide synthase expression in endothelial cells. Circ. Res. 102, 538–545 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Parmar, K. M. et al. Statins exert endothelial atheroprotective effects via the KLF2 transcription factor. J. Biol. Chem. 280, 26714–26719 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Nakajima, H. & Mochizuki, N. Flow pattern-dependent endothelial cell responses through transcriptional regulation. Cell Cycle 16, 1893–1901 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kempe, S., Kestler, H., Lasar, A. & Wirth, T. NF-κB controls the global pro-inflammatory response in endothelial cells: evidence for the regulation of a pro-atherogenic program. Nucleic Acids Res. 33, 5308–5319 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. van Uden, P., Kenneth, N. S. & Rocha, S. Regulation of hypoxia-inducible factor-1α by NF-κB. Biochem. J. 412, 477–484 (2008).

    Article  PubMed  Google Scholar 

  127. Feng, S. et al. Mechanical activation of hypoxia-inducible factor 1α drives endothelial dysfunction at atheroprone sites. Arterioscler. Thromb. Vasc. Biol. 37, 2087–2101 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Fernandez Esmerats, J. et al. Disturbed flow increases UBE2C (ubiquitin E2 ligase C) via loss of miR-483-3p, inducing aortic valve calcification by the pVHL (von Hippel-Lindau protein) and HIF-1α (hypoxia-inducible factor-1α) pathway in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 39, 467–481 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Villa-Roel, N. et al. Hypoxia inducible factor 1α inhibitor PX-478 reduces atherosclerosis in mice. Atherosclerosis 344, 20–30 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wu, D. et al. HIF-1alpha is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium. eLife https://doi.org/10.7554/eLife.25217 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Wang, K.-C. et al. Flow-dependent YAP/TAZ activities regulate endothelial phenotypes and atherosclerosis. Proc. Natl Acad. Sci. USA 113, 11525–11530 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer cell 29, 783–803 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Demos, C. et al. Sox13 is a novel flow-sensitive transcription factor that prevents inflammation by repressing chemokine expression in endothelial cells. Front. Cardiovasc. Med. 9, 979745 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dunn, J. et al. Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis. J. Clin. Invest. 124, 3187–3199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chen, X. et al. Plasma metabolomics reveals biomarkers of the atherosclerosis. J. Sep. Sci. 33, 2776–2783 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Goveia, J., Stapor, P. & Carmeliet, P. Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease. EMBO Mol. Med. 6, 1105–1120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Wu, J. et al. Proteomic identification of endothelial proteins isolated in situ from atherosclerotic aorta via systemic perfusion. J. Proteome Res. 6, 4728–4736 (2007).

    Article  CAS  PubMed  Google Scholar 

  140. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kumar, S., Williams, D., Sur, S., Wang, J.-Y. & Jo, H. Role of flow-sensitive microRNAs and long noncoding RNAs in vascular dysfunction and atherosclerosis. Vasc. Pharmacol. 114, 76–92 (2019).

    Article  CAS  Google Scholar 

  142. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Williams, D. et al. Stable flow-induced expression of KLK10 inhibits endothelial inflammation and atherosclerosis. eLife https://doi.org/10.7554/eLife.72579 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Liu, R., Qu, S., Xu, Y., Jo, H. & Dai, Z. Spatial control of robust transgene expression in mouse artery endothelium under ultrasound guidance. Signal Transduct. Target. Ther. 7, 225 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Jiang, Y. Z. et al. Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-like factor 4 promoter in vitro and in vivo. Circ. Res. 115, 32–43 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhou, J., Li, Y.-S., Wang, K.-C. & Chien, S. Epigenetic mechanism in regulation of endothelial function by disturbed flow: induction of DNA hypermethylation by DNMT1. Cell. Mol. Bioeng. 7, 218–224 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Firasat, S., Hecker, M., Binder, L. & Asif, A. R. Advances in endothelial shear stress proteomics. Expert. Rev. Proteom. 11, 611–619 (2014).

    Article  CAS  Google Scholar 

  148. Burghoff, S. & Schrader, J. R. Secretome of human endothelial cells under shear stress. J. Proteome Res. 10, 1160–1169 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Bibli, S. I. et al. Mapping the endothelial cell S-sulfhydrome highlights the crucial role of integrin sulfhydration in vascular function. Circulation 143, 935–948 (2021).

    Article  CAS  PubMed  Google Scholar 

  150. Son, D. J. et al. The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. Nat. Commun. 4, 3000 (2013).

    Article  PubMed  Google Scholar 

  151. Weiler, P., Van den Berge, K., Street, K. & Tiberi, S. A guide to trajectory inference and RNA velocity. Methods Mol. Biol. 2584, 269–292 (2023).

    Article  CAS  PubMed  Google Scholar 

  152. Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e21 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Chen, P. Y. et al. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J. Clin. Invest. 125, 4514–4528 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Frid, M. G., Kale, V. A. & Stenmark, K. R. Mature vascular endothelium can give rise to smooth muscle cells via endothelial-mesenchymal transdifferentiation: in vitro analysis. Circ. Res. 90, 1189–1196 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Cooley, B. C. et al. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci. Transl. Med. 6, 227ra234 (2014).

    Article  Google Scholar 

  156. Kouzbari, K. et al. Oscillatory shear potentiates latent TGF-β1 activation more than steady shear as demonstrated by a novel force generator. Sci. Rep. 9, 6065 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Egorova, A. D. et al. Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ. Res. 108, 1093–1101 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhang, Y., Qiu, J., Wang, X., Zhang, Y. & Xia, M. AMP-activated protein kinase suppresses endothelial cell inflammation through phosphorylation of transcriptional coactivator p300. Arterioscler. Thromb. Vasc. Biol. 31, 2897–2908 (2011).

    Article  CAS  PubMed  Google Scholar 

  159. Cheng, C. K. et al. Activation of AMPK/miR-181b axis alleviates endothelial dysfunction and vascular inflammation in diabetic mice. Antioxidants https://doi.org/10.3390/antiox11061137 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Fisslthaler, B., Fleming, I., Keseru, B., Walsh, K. & Busse, R. Fluid shear stress and NO decrease the activity of the hydroxy-methylglutaryl coenzyme A reductase in endothelial cells via the AMP-activated protein kinase and FoxO1. Circ. Res. 100, e12–e21 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Evrard, S. et al. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat. Commun. 7, 11853 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Shao, Y. et al. Endothelial immunity trained by coronavirus infections, DAMP stimulations and regulated by anti-oxidant NRF2 may contribute to inflammations, myelopoiesis, COVID-19 cytokine storms and thromboembolism. Front. Immunol. 12, 653110 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Plein, A., Fantin, A., Denti, L., Pollard, J. W. & Ruhrberg, C. Erythro-myeloid progenitors contribute endothelial cells to blood vessels. Nature 562, 223–228 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kumar, S. et al. Atorvastatin and blood flow regulate expression of distinctive sets of genes in mouse carotid artery endothelium. Curr. Top. Membr. 87, 97–130 (2021).

    Article  CAS  PubMed  Google Scholar 

  165. Sangwung, P. et al. KLF2 and KLF4 control endothelial identity and vascular integrity. JCI Insight 2, e91700 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Lee, G. H. et al. Betulinic acid induces eNOS expression via the AMPK-dependent KLF2 signaling pathway. J. Agric. Food Chem. 68, 14523–14530 (2020).

    Article  CAS  PubMed  Google Scholar 

  167. Davies, J. E. et al. Using Yoda-1 to mimic laminar flow in vitro: a tool to simplify drug testing. Biochem. Pharmacol. 168, 473–480 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Syeda, R. et al. Chemical activation of the mechanotransduction channel Piezo1. eLife https://doi.org/10.7554/eLife.07369 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Wang, Y. et al. A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. Nat. Commun. 9, 1300 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Wu, W. et al. Flow-dependent regulation of Krüppel-like factor 2 is mediated by microRNA-92a. Circulation 124, 633–641 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Meng, X., Yin, J., Yu, X. & Guo, Y. MicroRNA-205-5p promotes unstable atherosclerotic plaque formation in vivo. Cardiovasc. Drugs Ther. 34, 25–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  173. Topper, J. N., Cai, J. X., Falb, D. & Gimbrone, M. A. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc. Natl Acad. Sci. USA 93, 10417–10422 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 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).

    Article  CAS  PubMed  Google Scholar 

  175. Huddleson, J. P., Srinivasan, S., Ahmad, N. & Lingrel, J. B. Fluid shear stress induces endothelial KLF2 gene expression through a defined promoter region. Biol. Chem. 385, 723–729 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Hamik, A. et al. Kruppel-like factor 4 regulates endothelial inflammation. J. Biol. Chem. 282, 13769–13779 (2007).

    Article  CAS  PubMed  Google Scholar 

  177. Topper, J. N. & Gimbrone, M. A. Jr. Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol. Med. Today 5, 40–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  178. Stöhr, R. et al. Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice. Atherosclerosis 235, 438–443 (2014).

    Article  PubMed  Google Scholar 

  179. Son, D. J. et al. Interleukin-32α inhibits endothelial inflammation, vascular smooth muscle cell activation, and atherosclerosis by upregulating Timp3 and Reck through suppressing microRNA-205 biogenesis. Theranostics 7, 2186–2203 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Wang, Y. et al. ZBTB46 is a shear-sensitive transcription factor inhibiting endothelial cell proliferation via gene expression regulation of cell cycle proteins. Lab. Investig. https://doi.org/10.1038/s41374-018-0060-5 (2018).

    Article  PubMed  Google Scholar 

  181. Kim, C. W. et al. Anti-inflammatory and antiatherogenic role of BMP receptor II in endothelial cells. Arterioscler. Thromb. Vasc. Biol. https://doi.org/10.1161/ATVBAHA.112.300287 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Hosoya, T. et al. Differential responses of the Nrf2-Keap1 system to laminar and oscillatory shear stresses in endothelial cells. J. Biol. Chem. 280, 27244–27250 (2005).

    Article  CAS  PubMed  Google Scholar 

  183. Shyy, Y. J., Hsieh, H. J., Usami, S. & Chien, S. Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium. Proc. Natl Acad. Sci. USA 91, 4678–4682 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Miriyala, S. et al. Bone morphogenic protein-4 induces hypertension in mice: role of noggin, vascular NADPH oxidases, and impaired vasorelaxation. Circulation 113, 2818–2825 (2006).

    Article  CAS  PubMed  Google Scholar 

  185. Vendrov, A. E., Madamanchi, N. R., Hakim, Z. S., Rojas, M. & Runge, M. S. Thrombin and NAD(P)H oxidase-mediated regulation of CD44 and BMP4-Id pathway in VSMC, restenosis, and atherosclerosis. Circ. Res. 98, 1254–1263 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. 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).

    Article  CAS  PubMed  Google Scholar 

  187. Son, J. W. et al. Serum BMP-4 levels in relation to arterial stiffness and carotid atherosclerosis in patients with type 2 diabetes. Biomark. Med. 5, 827–835 (2011).

    Article  CAS  PubMed  Google Scholar 

  188. Koga, M. et al. BMP4 is increased in the aortas of diabetic ApoE knockout mice and enhances uptake of oxidized low density lipoprotein into peritoneal macrophages. J. Inflamm. 10, 32 (2013).

    Article  Google Scholar 

  189. Jank, M. et al. Platelet bone morphogenetic protein-4 mediates vascular inflammation and neointima formation after arterial injury. Cells https://doi.org/10.3390/cells10082027 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Csiszar, A., Labinskyy, N., Jo, H., Ballabh, P. & Ungvari, Z. Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 295, H569–H577 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 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).

    Article  CAS  PubMed  Google Scholar 

  192. Nagel, T., Resnick, N., Atkinson, W. J., Dewey, C. F. Jr. & Gimbrone, M. A. Jr. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J. Clin. Investig. 94, 885–891 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Pamukcu, B., Lip, G. Y. & Shantsila, E. The nuclear factor–kappa B pathway in atherosclerosis: a potential therapeutic target for atherothrombotic vascular disease. Thromb. Res. 128, 117–123 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. Barnes, P. J. & Karin, M. Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    Article  CAS  PubMed  Google Scholar 

  195. van der Heiden, K. et al. Role of nuclear factor κB in cardiovascular health and disease. Clin. Sci. 118, 593–605 (2010).

    Article  Google Scholar 

  196. Hajra, L. et al. The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc. Natl Acad. Sci. USA 97, 9052–9057 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. De Keulenaer, G. W. et al. Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ. Res. 82, 1094–1101 (1998).

    Article  PubMed  Google Scholar 

  198. Goettsch, C. et al. Arterial flow reduces oxidative stress via an antioxidant response element and Oct-1 binding site within the NADPH oxidase 4 promoter in endothelial cells. Basic Res. Cardiol. 106, 551–561 (2011).

    Article  CAS  PubMed  Google Scholar 

  199. Gray, S. P. et al. NADPH oxidase 1 plays a key role in diabetes mellitus-accelerated atherosclerosis. Circulation 127, 1888–1902 (2013).

    Article  CAS  PubMed  Google Scholar 

  200. Jeon, H. & Boo, Y. C. Laminar shear stress enhances endothelial cell survival through a NADPH oxidase 2-dependent mechanism. Biochem. Biophys. Res. Commun. 430, 460–465 (2013).

    Article  CAS  PubMed  Google Scholar 

  201. Craige, S. M. et al. Endothelial NADPH oxidase 4 protects ApoE-/- mice from atherosclerotic lesions. Free Radic. Biol. Med. 89, 1–7 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Kim, J., Seo, M., Kim, S. K. & Bae, Y. S. Flagellin-induced NADPH oxidase 4 activation is involved in atherosclerosis. Sci. Rep. 6, 25437 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Langbein, H. et al. NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice. Eur. Heart J. 37, 1753–1761 (2016).

    Article  CAS  PubMed  Google Scholar 

  204. Galis, Z. S., Sukhova, G. K., Lark, M. W. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Investig. 94, 2493–2503 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Magid, R., Murphy, T. J. & Galis, Z. S. Expression of matrix metalloproteinase-9 in endothelial cells is differentially regulated by shear stress. Role of c-Myc. J. Biol. Chem. 278, 32994–32999 (2003).

    Article  CAS  PubMed  Google Scholar 

  206. Sho, E. et al. Arterial enlargement in response to high flow requires early expression of matrix metalloproteinases to degrade extracellular matrix. Exp. Mol. Pathol. 73, 142–153 (2002).

    Article  CAS  PubMed  Google Scholar 

  207. Yun, S. et al. Transcription factor Sp1 phosphorylation induced by shear stress inhibits membrane type 1-matrix metalloproteinase expression in endothelium. J. Biol. Chem. 277, 34808–34814 (2002).

    Article  CAS  PubMed  Google Scholar 

  208. Volger, O. L. et al. Distinctive expression of chemokines and transforming growth factor-β signaling in human arterial endothelium during atherosclerosis. Am. J. Pathol. 171, 326–337 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Akimoto, S., Mitsumata, M., Sasaguri, T. & Yoshida, Y. Laminar shear stress inhibits vascular endothelial cell proliferation by inducing cyclin-dependent kinase inhibitor p21Sdi1/Cip1/Waf1. Circ. Res. 86, 185–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  210. Kadohama, T., Nishimura, K., Hoshino, Y., Sasajima, T. & Sumpio, B. E. Effects of different types of fluid shear stress on endothelial cell proliferation and survival. J. Cell Physiol. 212, 244–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  211. Bao, X., Lu, C. & Frangos, J. A. Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 281, H22–H29 (2001).

    Article  CAS  PubMed  Google Scholar 

  212. Jo, H. et al. Differential effect of shear stress on extracellular signal-regulated kinase and N-terminal Jun kinase in endothelial cells. Gi2- and Gβ/γ-dependent signaling pathways. J. Biol. Chem. 272, 1395–1401 (1997).

    Article  CAS  PubMed  Google Scholar 

  213. Moura, R. et al. Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE−/− mice. Circ. Res. 103, 1181–1189 (2008).

    Article  CAS  PubMed  Google Scholar 

  214. Hu, S. et al. Vascular semaphorin 7A upregulation by disturbed flow promotes atherosclerosis through endothelial β1 integrin. Arterioscler. Thromb. Vasc. Biol. 38, 335–343 (2018).

    Article  CAS  PubMed  Google Scholar 

  215. Henn, D. et al. MicroRNA-regulated pathways of flow-stimulated angiogenesis and vascular remodeling in vivo. J. Transl. Med. 17, 22 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Green, J. P. et al. Atheroprone flow activates inflammation via endothelial ATP-dependent P2X7-p38 signalling. Cardiovasc. Res. 114, 324–335 (2018).

    Article  CAS  PubMed  Google Scholar 

  217. Glaser, S. F. et al. The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. Proc. Natl Acad. Sci. USA 117, 4180–4187 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  PubMed  Google Scholar 

  219. Björck, 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).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Yeh, C.-F. et al. Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo. Sci. Adv. 8, eabl8096 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Qin, X. et al. MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc. Natl Acad. Sci. USA 107, 3240–3244 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Chen, H., Li, X., Liu, S., Gu, L. & Zhou, X. MircroRNA-19a promotes vascular inflammation and foam cell formation by targeting HBP-1 in atherogenesis. Sci. Rep. 7, 12089 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Wang, K. C. et al. Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc. Natl Acad. Sci. USA 107, 3234–3239 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Iaconetti, C. et al. Down-regulation of miR-23b induces phenotypic switching of vascular smooth muscle cells in vitro and in vivo. Cardiovasc. Res. 107, 522–533 (2015).

    Article  CAS  PubMed  Google Scholar 

  226. Melo, S. A. & Kalluri, R. Angiogenesis is controlled by miR-27b associated with endothelial tip cells. Blood 119, 2439–2440 (2012).

    Article  CAS  PubMed  Google Scholar 

  227. Demolli, S. et al. Shear stress-regulated miR-27b controls pericyte recruitment by repressing SEMA6A and SEMA6D. Cardiovasc. Res. 113, 681–691 (2017).

    Article  CAS  PubMed  Google Scholar 

  228. Suzuki, H. I. et al. Regulation of TGF-β-mediated endothelial-mesenchymal transition by microRNA-27. J. Biochem. 161, 417–420 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Zeng, X., Huang, C., Senavirathna, L., Wang, P. & Liu, L. miR-27b inhibits fibroblast activation via targeting TGFβ signaling pathway. BMC Cell Biol. 18, 9 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Chen, K. et al. MicroRNA-101 mediates the suppressive effect of laminar shear stress on mTOR expression in vascular endothelial cells. Biochem. Biophys. Res. Commun. 427, 138–142 (2012).

    Article  CAS  PubMed  Google Scholar 

  231. Kim, J. H. et al. Hypoxia-responsive microRNA-101 promotes angiogenesis via heme oxygenase-1/vascular endothelial growth factor axis by targeting cullin 3. Antioxid. Redox Signal. 21, 2469–2482 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Zhang, N. et al. MicroRNA-101 overexpression by IL-6 and TNF-α inhibits cholesterol efflux by suppressing ATP-binding cassette transporter A1 expression. Exp. Cell Res. 336, 33–42 (2015).

    Article  CAS  PubMed  Google Scholar 

  233. Cordes, K. R. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460, 705–710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Kohlstedt, K. et al. AMP-activated protein kinase regulates endothelial cell angiotensin-converting enzyme expression via p53 and the post-transcriptional regulation of microRNA-143/145. Circ. Res. 112, 1150–1158 (2013).

    Article  CAS  PubMed  Google Scholar 

  235. Sala, F. et al. MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr−/− mice. Thromb. Haemost. 112, 796–802 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  236. Climent, M. et al. TGFβ triggers miR-143/145 transfer from smooth muscle cells to endothelial cells, thereby modulating vessel stabilization. Circ. Res. 116, 1753–1764 (2015).

    Article  CAS  PubMed  Google Scholar 

  237. Zernecke, A. et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009).

    Article  PubMed  Google Scholar 

  238. Zhou, J. et al. Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ. Res. 113, 40–51 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Schober, A. et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat. Med. 20, 368–376 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Wang, Y. et al. MicroRNA-126 attenuates palmitate-induced apoptosis by targeting TRAF7 in HUVECs. Mol. Cell. Biochem. 399, 123–130 (2015).

    Article  CAS  PubMed  Google Scholar 

  241. Tang, S. T., Wang, F., Shao, M., Wang, Y. & Zhu, H. Q. MicroRNA-126 suppresses inflammation in endothelial cells under hyperglycemic condition by targeting HMGB1. Vasc. Pharmacol. 88, 48–55 (2017).

    Article  CAS  Google Scholar 

  242. Cerutti, C. et al. MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium. Sci. Rep. 7, 45284 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Tang, F. & Yang, T. L. MicroRNA-126 alleviates endothelial cells injury in atherosclerosis by restoring autophagic flux via inhibiting of PI3K/Akt/mTOR pathway. Biochem. Biophys. Res. Commun. 495, 1482–1489 (2018).

    Article  CAS  PubMed  Google Scholar 

  244. Bonauer, A. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324, 1710–1713 (2009).

    Article  CAS  PubMed  Google Scholar 

  245. Fang, Y. & Davies, P. F. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler. Thromb. Vasc. Biol. 32, 979–987 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Loyer, X. et al. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ. Res. 114, 434–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  247. Ni, C. W., Qiu, H. & Jo, H. MicroRNA-663 upregulated by oscillatory shear stress plays a role in inflammatory response of endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 300, H1762–H1769 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Afonyushkin, T., Oskolkova, O. V. & Bochkov, V. N. Permissive role of miR-663 in induction of VEGF and activation of the ATF4 branch of unfolded protein response in endothelial cells by oxidized phospholipids. Atherosclerosis 225, 50–55 (2012).

    Article  CAS  PubMed  Google Scholar 

  249. Kheirolomoom, A. et al. Multifunctional nanoparticles facilitate molecular targeting and miRNA delivery to inhibit atherosclerosis in ApoE−/− mice. ACS Nano 9, 8885–8897 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Cheng, Y. & Zhang, C. MicroRNA-21 in cardiovascular disease. J. Cardiovasc. Transl. Res. 3, 251–255 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  251. Weber, M., Baker, M. B., Moore, J. P. & Searles, C. D. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem. Biophys. Res. Commun. 393, 643–648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Buscaglia, L. E. B. & Li, Y. Apoptosis and the target genes of microRNA-21. Chin. J. Cancer 30, 371–380 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  253. Zhou, J. et al. MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proc. Natl Acad. Sci. USA 108, 10355–10360 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. McDonald, R. A. et al. miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation. Eur. Heart J. 34, 1636–1643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Li, S. et al. MicroRNA-21 negatively regulates Treg cells through a TGF-β1/Smad-independent pathway in patients with coronary heart disease. Cell. Physiol. Biochem. 37, 866–878 (2015).

    Article  CAS  PubMed  Google Scholar 

  256. Sun, H. X. et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension 60, 1407–1414 (2012).

    Article  CAS  PubMed  Google Scholar 

  257. Weber, M., Kim, S., Patterson, N., Rooney, K. & Searles, C. D. MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 306, H1192–H1203 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. He, S., Yang, L., Li, D. & Li, M. Kruppel-like factor 2-mediated suppression of microRNA-155 reduces the proinflammatory activation of macrophages. PLoS ONE 10, e0139060 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Zhang, H. et al. Genistein protects against ox-LDL-induced inflammation through microRNA-155/SOCS1-mediated repression of NF-κB signaling pathway in HUVECs. Inflammation 40, 1450–1459 (2017).

    Article  CAS  PubMed  Google Scholar 

  260. Nazari-Jahantigh, M. et al. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J. Clin. Invest. 122, 4190–4202 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Michalik, K. M. et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res. 114, 1389–1397 (2014).

    Article  CAS  PubMed  Google Scholar 

  262. Wang, C., Qu, Y., Suo, R. & Zhu, Y. Long non-coding RNA MALAT1 regulates angiogenesis following oxygen-glucose deprivation/reoxygenation. J. Cell. Mol. Med. https://doi.org/10.1111/jcmm.14204 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  263. Leisegang, M. S. et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation 136, 65–79 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Huang, T. S. et al. LINC00341 exerts an anti-inflammatory effect on endothelial cells by repressing VCAM1. Physiol. Genomics 49, 339–345 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Josipovic, I. et al. Long noncoding RNA LISPR1 is required for S1P signaling and endothelial cell function. J. Mol. Cell. Cardiol. 116, 57–68 (2018).

    Article  CAS  PubMed  Google Scholar 

  266. Man, H. S. J. et al. Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA. Proc. Natl Acad. Sci. USA 115, 2401–2406 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I.A.T. is supported by NIH grant 5F31HL149285-03. K.I.B. is supported by NIH grants 5T32HL007745 and F32HL167625. H.J. is supported by NIH grants HL119798, HL139757 and HL151358. H.J. is also supported by the Wallace H. Coulter Distinguished Faculty Professorship.

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  1. These authors contributed equally: Ian A. Tamargo; Kyung In Baek.

Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA

    Ian A. Tamargo, Kyung In Baek, Yerin Kim, Christian Park & Hanjoong Jo

  2. Molecular and Systems Pharmacology Program, Emory University, Atlanta, GA, USA

    Ian A. Tamargo & Hanjoong Jo

  3. Department of Medicine, Emory University School, Atlanta, GA, USA

    Hanjoong Jo

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Tamargo, I.A., Baek, K.I., Kim, Y. et al. Flow-induced reprogramming of endothelial cells in atherosclerosis. Nat Rev Cardiol 20, 738–753 (2023). https://doi.org/10.1038/s41569-023-00883-1

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