1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Physiology
  4. Volume 85, 2023
  5. Article

Annual Review of Physiology

Volume 85, 2023

Endothelial to Mesenchymal Transition in Health and Disease

Abstract

The endothelium is one of the largest organ systems in the body, and data continue to emerge regarding the importance of endothelial cell (EC) dysfunction in vascular aging and a range of cardiovascular diseases (CVDs). Over the last two decades and as a process intimately related to EC dysfunction, an increasing number of studies have also implicated endothelial to mesenchymal transition (EndMT) as a potentially disease-causal pathobiologic process that is involved in a multitude of differing CVDs. However, EndMT is also involved in physiologic processes (e.g., cardiac development), and transient EndMT may contribute to vascular regeneration in certain contexts. Given that EndMT involves a major alteration in the EC-specific molecular program, and that it potentially contributes to CVD pathobiology, the clinical translation opportunities are significant, but further molecular and translational research is needed to see these opportunities realized.

Keyword(s): cardiovascular, EndMT, endothelial, endothelial to mesenchymal transition
Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-032222-080806
2023-02-10
2024-05-10
Loading full text...

Full text loading...

/deliver/fulltext/physiol/85/1/annurev-physiol-032222-080806.html?itemId=/content/journals/10.1146/annurev-physiol-032222-080806&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Foy AJ, Mandrola JM. 2018. Heavy heart: the economic burden of heart disease in the United States now and in the future. Prim. Care 45:17–24
     [Google Scholar]
  2. 2.
    Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW et al. 2019. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation 139:e56–528Erratum 2020. Circulation 141:e33
     [Google Scholar]
  3. 3.
    Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E et al. 2019. Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73:190–209
     [Google Scholar]
  4. 4.
    Hulshoff MS, del Monte-Nieto G, Kovacic J, Krenning G. 2019. Non-coding RNA in endothelial-to-mesenchymal transition. Cardiovasc. Res. 115:1716–31
     [Google Scholar]
  5. 5.
    Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V. 2012. Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease. Circulation 125:1795–808
     [Google Scholar]
  6. 6.
    Lecce L, Xu Y, V'Gangula B, Chandel N, Pothula V et al. 2021. Histone deacetylase 9 promotes endothelial-mesenchymal transition and an unfavorable atherosclerotic plaque phenotype. J. Clin. Investig. 131:e131178
     [Google Scholar]
  7. 7.
    Trelstad RL, Hay ED, Revel JD. 1967. Cell contact during early morphogenesis in the chick embryo. Dev. Biol. 16:78–106
     [Google Scholar]
  8. 8.
    Ubil E, Duan J, Pillai IC, Rosa-Garrido M, Wu Y et al. 2014. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature 514:585–90
     [Google Scholar]
  9. 9.
    Samavarchi-Tehrani P, Golipour A, David L, Sung HK, Beyer TA et al. 2010. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7:64–77
     [Google Scholar]
  10. 10.
    Sabbineni H, Verma A, Somanath PR. 2018. Isoform-specific effects of transforming growth factor beta on endothelial-to-mesenchymal transition. J. Cell. Physiol. 233:8418–28
     [Google Scholar]
  11. 11.
    Attisano L, Wrana JL. 2000. Smads as transcriptional co-modulators. Curr. Opin. Cell Biol. 12:235–43
     [Google Scholar]
  12. 12.
    Zhu HT, Kavsak P, Abdollah S, Wrana JL, Thomsen GH. 1999. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400:687–93
     [Google Scholar]
  13. 13.
    Kokudo T, Suzuki Y, Yoshimatsu Y, Yamazaki T, Watabe T, Miyazono K. 2008. Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. J. Cell Sci. 121:3317–24
     [Google Scholar]
  14. 14.
    Cooley BC, Nevado J, Mellad J, Yang D, St. Hilaire C et al. 2014. TGF-β signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Sci. Trans. Med. 6:227ra34
     [Google Scholar]
  15. 15.
    Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR et al. 2007. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13:952–61
     [Google Scholar]
  16. 16.
    Bai JX, Hao JF, Zhang XL, Cui HM, Han JM, Cao N. 2016. Netrin-1 attenuates the progression of renal dysfunction by blocking endothelial-to-mesenchymal transition in the 5/6 nephrectomy rat model. BMC Nephrol 17:47
     [Google Scholar]
  17. 17.
    Fleenor BS, Marshall KD, Rippe C, Seals DR. 2012. Replicative aging induces endothelial to mesenchymal transition in human aortic endothelial cells: potential role of inflammation. J. Vasc. Res. 49:59–64
     [Google Scholar]
  18. 18.
    Evrard SM, Lecce L, Michelis KC, Nomura-Kitabayashi A, Pandey G et al. 2016. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat. Commun. 7:11853
     [Google Scholar]
  19. 19.
    Song SS, Zhang M, Yi Z, Zhang HY, Shen TT et al. 2016. The role of PDGF-B/TGF-β 1/neprilysin network in regulating endothelial-to-mesenchymal transition in pulmonary artery remodeling. Cell. Signal. 28:1489–501
     [Google Scholar]
  20. 20.
    Yu L, Hébert MC, Zhang YE. 2002. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J 21:3749–59
     [Google Scholar]
  21. 21.
    Medici D, Potenta S, Kalluri R. 2011. Transforming growth factor-β2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem. J. 437:515–20
     [Google Scholar]
  22. 22.
    Sasaki N, Itakura Y, Toyoda M. 2020. Rapamycin promotes endothelial-mesenchymal transition during stress-induced premature senescence through the activation of autophagy. Cell Commun. Signal. 18:43
     [Google Scholar]
  23. 23.
    Chang AC, Fu Y, Garside VC, Niessen K, Chang L et al. 2011. Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev. Cell 21:288–300
     [Google Scholar]
  24. 24.
    Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M. 2004. The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18:901–11
     [Google Scholar]
  25. 25.
    Li L, Chen L, Zang J, Tang X, Liu Y et al. 2015. C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease. Metabolism 64:597–610
     [Google Scholar]
  26. 26.
    Lee WJ, Park JH, Shin JU, Noh H, Lew DH et al. 2015. Endothelial-to-mesenchymal transition induced by Wnt 3a in keloid pathogenesis. Wound Repair Regen 23:435–42
     [Google Scholar]
  27. 27.
    Weinstein N, Mendoza L, Alvarez-Buylla ER. 2020. A computational model of the endothelial to mesenchymal transition. Front. Genet. 11:40
     [Google Scholar]
  28. 28.
    Li W, Kang Y. 2016. Probing the fifty shades of EMT in metastasis. Trends Cancer 2:65–67
     [Google Scholar]
  29. 29.
    Vicovac L, Aplin JD. 1996. Epithelial-mesenchymal transition during trophoblast differentiation. Acta Anat. 156:202–16
     [Google Scholar]
  30. 30.
    Kovacic JC, Moore J, Herbert A, Ma D, Boehm M, Graham RM. 2008. Endothelial progenitor cells, angioblasts, and angiogenesis–old terms reconsidered from a current perspective. Trends Cardiov. Med. 18:45–51
     [Google Scholar]
  31. 31.
    Kovacic JC, Boehm M. 2009. Resident vascular progenitor cells: an emerging role for non-terminally differentiated vessel-resident cells in vascular biology. Stem. Cell Res 2:2–15
     [Google Scholar]
  32. 32.
    Nakano H, Liu XQ, Arshi A, Nakashima Y, van Handel B et al. 2013. Haemogenic endocardium contributes to transient definitive haematopoiesis. Nat. Commun. 4:1564
     [Google Scholar]
  33. 33.
    Eisenberg LM, Markwald RR. 1995. Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ. Res. 77:1–6
     [Google Scholar]
  34. 34.
    Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, Yanagisawa M. 2001. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev. Biol. 230:230–42
     [Google Scholar]
  35. 35.
    Arciniegas E, Neves CY, Carrillo LM, Zambrano EA, Ramirez R. 2005. Endothelial-mesenchymal transition occurs during embryonic pulmonary artery development. Endothelium 12:193–200
     [Google Scholar]
  36. 36.
    Xiong J, Kawagishi H, Yan Y, Liu J, Wells QS et al. 2018. A metabolic basis for endothelial-to-mesenchymal transition. Mol. Cell 69:689–98.e7
     [Google Scholar]
  37. 37.
    Frangogiannis NG, Kovacic JC. 2020. Extracellular matrix in ischemic heart disease, part 4/4: JACC Focus Seminar. J. Am. Coll. Cardiol. 75:2219–35
     [Google Scholar]
  38. 38.
    Ali SR, Ranjbarvaziri S, Talkhabi M, Zhao P, Subat A et al. 2014. Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ. Res. 115:625–35
     [Google Scholar]
  39. 39.
    Moore-Morris T, Guimarães-Camboa N, Banerjee I, Zambon AC, Kisseleva T et al. 2014. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J. Clin. Investig. 124:2921–34
     [Google Scholar]
  40. 40.
    Tian J, Zhang M, Suo M, Liu D, Wang X et al. 2021. Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF-β/Smad signalling in type 2 diabetic rats. J. Cell. Mol. Med. 25:7642–59
     [Google Scholar]
  41. 41.
    Wang Z, Stuckey DJ, Murdoch CE, Camelliti P, Lip GYH, Griffin M. 2018. Cardiac fibrosis can be attenuated by blocking the activity of transglutaminase 2 using a selective small-molecule inhibitor. Cell Death Dis 9:613
     [Google Scholar]
  42. 42.
    Zhang GH, Yu FC, Li Y, Wei Q, Song SS et al. 2017. Prolyl 4-hydroxylase domain protein 3 overexpression improved obstructive sleep apnea-induced cardiac perivascular fibrosis partially by suppressing endothelial-to-mesenchymal transition. J. Am. Heart Assoc. 6:e006680
     [Google Scholar]
  43. 43.
    Jeong D, Lee MA, Li Y, Yang DK, Kho C et al. 2016. Matricellular protein CCN5 reverses established cardiac fibrosis. J. Am. Coll. Cardiol. 67:1556–68
     [Google Scholar]
  44. 44.
    Zhang L, He J, Wang J, Liu J, Chen Z et al. 2021. Knockout RAGE alleviates cardiac fibrosis through repressing endothelial-to-mesenchymal transition (EndMT) mediated by autophagy. Cell Death Dis 12:470
     [Google Scholar]
  45. 45.
    Murdoch CE, Chaubey S, Zeng L, Yu B, Ivetic A et al. 2014. Endothelial NADPH oxidase-2 promotes interstitial cardiac fibrosis and diastolic dysfunction through proinflammatory effects and endothelial-mesenchymal transition. J. Am. Coll. Cardiol. 63:2734–41
     [Google Scholar]
  46. 46.
    Tombor LS, John D, Glaser SF, Luxan G, Forte E et al. 2021. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction. Nat. Commun. 12:681
     [Google Scholar]
  47. 47.
    Grande MT, Sanchez-Laorden B, Lopez-Blau C, De Frutos CA, Boutet A et al. 2015. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21:989–97
     [Google Scholar]
  48. 48.
    Tabas I, Garcia-Cardena G, Owens GK. 2015. Recent insights into the cellular biology of atherosclerosis. J. Cell Biol. 209:13–22
     [Google Scholar]
  49. 49.
    Furie MB, Mitchell RN. 2012. Plaque attack: one hundred years of atherosclerosis in The American Journal of Pathology. Am. J. Pathol. 180:2184–87
     [Google Scholar]
  50. 50.
    Insull W. 2009. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am. J. Med. 122:S3–14
     [Google Scholar]
  51. 51.
    Dejana E, Lampugnani MG. 2018. Endothelial cell transitions. Science 362:746–47
     [Google Scholar]
  52. 52.
    Kim M, Choi SH, Jin YB, Lee HJ, Ji YH et al. 2013. The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition. Int. J. Radiat. Biol. 89:356–63
     [Google Scholar]
  53. 53.
    Chen PY, Qin L, Baeyens N, Li G, Afolabi T et al. 2015. Endothelial-to-mesenchymal transition drives atherosclerosis progression. J. Clin. Investig. 125:4514–28
     [Google Scholar]
  54. 54.
    Li P, Ge J, Li H. 2020. Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease. Nat. Rev. Cardiol. 17:96–115
     [Google Scholar]
  55. 55.
    Chen PY, Qin L, Li G, Wang Z, Dahlman JE et al. 2019. Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis. Nat. Metab. 1:912–26
     [Google Scholar]
  56. 56.
    Miscianinov V, Martello A, Rose L, Parish E, Cathcart B et al. 2018. MicroRNA-148b targets the TGF-β pathway to regulate angiogenesis and endothelial-to-mesenchymal transition during skin wound healing. Mol. Ther. 26:1996–2007
     [Google Scholar]
  57. 57.
    Kolh P, Windecker S, Alfonso F, Collet JP, Cremer J et al. 2014. 2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur. Heart J. 35:2541–619
     [Google Scholar]
  58. 58.
    Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR et al. 2011. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 58:e123–210
     [Google Scholar]
  59. 59.
    Hess CN, Lopes RD, Gibson CM, Hager R, Wojdyla DM et al. 2014. Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV. Circulation 130:1445–51
     [Google Scholar]
  60. 60.
    Mehta RH, Ferguson TB, Lopes RD, Hafley GE, Mack MJ et al. 2011. Saphenous vein grafts with multiple versus single distal targets in patients undergoing coronary artery bypass surgery: one-year graft failure and five-year outcomes from the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV trial. Circulation 124:280–88
     [Google Scholar]
  61. 61.
    Parang P, Arora R. 2009. Coronary vein graft disease: pathogenesis and prevention. Can. J. Cardiol. 25:e57–62
     [Google Scholar]
  62. 62.
    Chen D, Zhang C, Chen J, Yang M, Afzal TA et al. 2021. miRNA-200c-3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts. J. Pathol. 253:209–24
     [Google Scholar]
  63. 63.
    Findeisen HM, Gizard F, Zhao Y, Qing H, Heywood EB et al. 2011. Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition. Arterioscler. Thromb. Vasc. Biol. 31:851–60
     [Google Scholar]
  64. 64.
    Song S, Kang SW, Choi C. 2010. Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1. Cardiovasc. Res. 85:241–49
     [Google Scholar]
  65. 65.
    Barst RJ, McGoon MD, Elliott CG, Foreman AJ, Miller DP, Ivy DD. 2012. Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Circulation 125:113–22
     [Google Scholar]
  66. 66.
    Hoeper MM, Humbert M, Souza R, Idrees M, Kawut SM et al. 2016. A global view of pulmonary hypertension. Lancet Respir. Med. 4:306–22
     [Google Scholar]
  67. 67.
    Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux C et al. 2015. Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131:1006–18
     [Google Scholar]
  68. 68.
    Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G et al. 2015. Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am. J. Pathol. 185:1850–58
     [Google Scholar]
  69. 69.
    Hopper RK, Moonen JR, Diebold I, Cao A, Rhodes CJ et al. 2016. In pulmonary arterial hypertension, reduced BMPR2 promotes endothelial-to-mesenchymal transition via HMGA1 and its target slug. Circulation 133:1783–94
     [Google Scholar]
  70. 70.
    Zhang H, Liu Y, Yan L, Du W, Zhang X et al. 2018. Bone morphogenetic protein-7 inhibits endothelial-mesenchymal transition in pulmonary artery endothelial cell under hypoxia. J. Cell. Physiol. 233:4077–90
     [Google Scholar]
  71. 71.
    Woo KV, Shen IY, Weinheimer CJ, Kovacs A, Nigro J et al. 2021. Endothelial FGF signaling is protective in hypoxia-induced pulmonary hypertension. J. Clin. Investig. 131:e141467
     [Google Scholar]
  72. 72.
    Li T, Zha L, Luo H, Li S, Zhao L et al. 2019. Galectin-3 mediates endothelial-to-mesenchymal transition in pulmonary arterial hypertension. Aging Dis 10:731–45
     [Google Scholar]
  73. 73.
    Monteiro JP, Rodor J, Caudrillier A, Scanlon JP, Spiroski AM et al. 2021. MIR503HG loss promotes endothelial-to-mesenchymal transition in vascular disease. Circ. Res. 128:1173–90
     [Google Scholar]
  74. 74.
    Paruchuri S, Yang JH, Aikawa E, Melero-Martin JM, Khan ZA et al. 2006. Human pulmonary valve progenitor cells exhibit endothelial/mesenchymal plasticity in response to vascular endothelial growth factor-A and transforming growth factor-β2. Circ. Res. 99:861–69
     [Google Scholar]
  75. 75.
    Balachandran K, Alford PW, Wylie-Sears J, Goss JA, Grosberg A et al. 2011. Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve. PNAS 108:19943–48
     [Google Scholar]
  76. 76.
    Wirrig EE, Yutzey KE. 2014. Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler. Thromb. Vasc. Biol. 34:737–41
     [Google Scholar]
  77. 77.
    Yutzey KE, Demer LL, Body SC, Huggins GS, Towler DA et al. 2014. Calcific aortic valve disease: a consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler. Thromb. Vasc. Biol. 34:2387–93
     [Google Scholar]
  78. 78.
    Hjortnaes J, Shapero K, Goettsch C, Hutcheson JD, Keegan J et al. 2015. Valvular interstitial cells suppress calcification of valvular endothelial cells. Atherosclerosis 242:251–60
     [Google Scholar]
  79. 79.
    Xu K, Xie S, Huang Y, Zhou T, Liu M et al. 2020. Cell-type transcriptome atlas of human aortic valves reveal cell heterogeneity and endothelial to mesenchymal transition involved in calcific aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 40:2910–21
     [Google Scholar]
  80. 80.
    Dal-Bianco JP, Aikawa E, Bischoff J, Guerrero JL, Handschumacher MD et al. 2009. Active adaptation of the tethered mitral valve: insights into a compensatory mechanism for functional mitral regurgitation. Circulation 120:334–42
     [Google Scholar]
  81. 81.
    Bartko PE, Dal-Bianco JP, Guerrero JL, Beaudoin J, Szymanski C et al. 2017. Effect of losartan on mitral valve changes after myocardial infarction. J. Am. Coll. Cardiol. 70:1232–44
     [Google Scholar]
  82. 82.
    Xu X, Friehs I, Zhong Hu T, Melnychenko I, Tampe B et al. 2015. Endocardial fibroelastosis is caused by aberrant endothelial to mesenchymal transition. Circ. Res. 116:857–66
     [Google Scholar]
  83. 83.
    Zhang H, Huang XZ, Liu K, Tang J, He LJ et al. 2017. Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium. Cell Res 27:1157–77
     [Google Scholar]
  84. 84.
    Purevjav E, Varela J, Morgado M, Kearney DL, Li H et al. 2010. Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. J. Am. Coll. Cardiol. 56:1493–502
     [Google Scholar]
  85. 85.
    Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C et al. 2013. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498:492–96
     [Google Scholar]
  86. 86.
    Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM et al. 2016. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 532:122–26
     [Google Scholar]
  87. 87.
    Nussbaum SR, Carter MJ, Fife CE, DaVanzo J, Haught R et al. 2018. An economic evaluation of the impact, cost, and Medicare policy implications of chronic nonhealing wounds. Value Health 21:27–32
     [Google Scholar]
  88. 88.
    Hultgren NW, Fang JS, Ziegler ME, Ramirez RN, Phan DTT et al. 2020. Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis. Nat. Commun. 11:5400
     [Google Scholar]
  89. 89.
    Welch-Reardon KM, Ehsan SM, Wang K, Wu N, Newman AC et al. 2014. Angiogenic sprouting is regulated by endothelial cell expression of Slug. J. Cell Sci. 127:2017–28
     [Google Scholar]
  90. 90.
    Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A. 2018. Mechanisms of vascular aging. Circ. Res. 123:849–67
     [Google Scholar]
  91. 91.
    Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P et al. 2011. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am. J. Physiol. Heart Circ. Physiol. 301:H363–72
     [Google Scholar]
  92. 92.
    Chen Y, Yuan T, Zhang H, Yan Y, Wang D et al. 2017. Activation of Nrf2 attenuates pulmonary vascular remodeling via inhibiting endothelial-to-mesenchymal transition: an insight from a plant polyphenol. Int. J. Biol. Sci. 13:1067–81
     [Google Scholar]
  93. 93.
    Weichhart T. 2018. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology 64:127–34
     [Google Scholar]
  94. 94.
    Kuosmanen SM, Kansanen E, Sihvola V, Levonen AL. 2017. MicroRNA profiling reveals distinct profiles for tissue-derived and cultured endothelial cells. Sci. Rep. 7:10943
     [Google Scholar]
  95. 95.
    Piera-Velazquez S, Jimenez SA. 2019. Endothelial to mesenchymal transition: role in physiology and in the pathogenesis of human diseases. Physiol. Rev. 99:1281–324
     [Google Scholar]
  96. 96.
    Kalucka J, de Rooij L, Goveia J, Rohlenova K, Dumas SJ et al. 2020. Single-cell transcriptome atlas of murine endothelial cells. Cell 180:764–79.e20
     [Google Scholar]
  97. 97.
    Rohlenova K, Goveia J, Garcia-Caballero M, Subramanian A, Kalucka J et al. 2020. Single-cell RNA sequencing maps endothelial metabolic plasticity in pathological angiogenesis. Cell Metab 31:862–77.e14
     [Google Scholar]
  98. 98.
    Kalluri AS, Vellarikkal SK, Edelman ER, Nguyen L, Subramanian A et al. 2019. Single-cell analysis of the normal mouse aorta reveals functionally distinct endothelial cell populations. Circulation 140:147–63
     [Google Scholar]
  99. 99.
    Kan H, Zhang K, Mao AQ, Geng L, Gao MR et al. 2021. Single-cell transcriptome analysis reveals cellular heterogeneity in the ascending aortas of normal and high-fat diet-fed mice. Exp. Mol. Med. 53:1379–89
     [Google Scholar]
  100. 100.
    Zhao P, Yao Q, Zhang PJ, The E, Zhai Y et al. 2021. Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip. Sci. Adv. 7:eabg1694
     [Google Scholar]
  101. 101.
    Medici D, Shore EM, Lounev VY, Kaplan FS, Kalluri R, Olsen BR. 2010. Conversion of vascular endothelial cells into multipotent stem-like cells. Nat. Med. 16:1400–6
     [Google Scholar]
  102. 102.
    Santamaria PG, Moreno-Bueno G, Portillo F, Cano A. 2017. EMT: present and future in clinical oncology. Mol. Oncol. 11:718–38
     [Google Scholar]
  103. 103.
    Fan LC, Shiau CW, Tai WT, Hung MH, Chu PY et al. 2015. SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma. Oncogene 34:5252–63
     [Google Scholar]
  104. 104.
    George SJ, Wan S, Hu J, MacDonald R, Johnson JL, Baker AH. 2011. Sustained reduction of vein graft neointima formation by ex vivo TIMP-3 gene therapy. Circulation 124:S135–42
     [Google Scholar]
  105. 105.
    George SJ, Lloyd CT, Angelini GD, Newby AC, Baker AH. 2000. Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3. Circulation 101:296–304
     [Google Scholar]
  106. 106.
    Wang D, Xu X, Zhao M, Wang X. 2020. Accelerated miniature swine models of advanced atherosclerosis: a review based on morphology. Cardiovasc. Pathol. 49:107241
     [Google Scholar]
  107. 107.
    Kim M, Kim HB, Park DS, Cho KH, Hyun DY et al. 2021. A model of atherosclerosis using nicotine with balloon overdilation in a porcine. Sci. Rep. 11:13695
     [Google Scholar]
  108. 108.
    Lin K, Luo W, Yan JQ, Shen SY, Shen QR et al. 2021. TLR2 regulates angiotensin II-induced vascular remodeling and EndMT through NF-κB signaling. Aging 13:2553–74
     [Google Scholar]
  109. 109.
    Luna-Zurita L, Prados B, Grego-Bessa J, Luxan G, del Monte G et al. 2010. Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation. J. Clin. Investig. 120:3493–507
     [Google Scholar]
  110. 110.
    Zhang L, Li YM, Zeng XX, Wang XY, Chen SK et al. 2018. Galectin-3-mediated transdifferentiation of pulmonary artery endothelial cells contributes to hypoxic pulmonary vascular remodeling. Cell. Physiol. Biochem. 51:763–77
     [Google Scholar]
  111. 111.
    Mahmoud MM, Serbanovic-Canic J, Feng S, Souilhol C, Xing R et al. 2017. Shear stress induces endothelial-to-mesenchymal transition via the transcription factor Snail. Sci. Rep. 7:3375
     [Google Scholar]
  112. 112.
    Mahmoud MM, Kim HR, Xing R, Hsiao S, Mammoto A et al. 2016. TWIST1 integrates endothelial responses to flow in vascular dysfunction and atherosclerosis. Circ. Res. 119:450–62
     [Google Scholar]
  113. 113.
    Rivera-Feliciano J, Lee KH, Kong SW, Rajagopal S, Ma Q et al. 2006. Development of heart valves requires Gata4 expression in endothelial-derived cells. Development 133:3607–18
     [Google Scholar]
  114. 114.
    Chen L, Shang C, Wang B, Wang G, Jin Z et al. 2021. HDAC3 inhibitor suppresses endothelial-to-mesenchymal transition via modulating inflammatory response in atherosclerosis. Biochem. Pharmacol. 192:114716
     [Google Scholar]
  115. 115.
    Otsuki S, Saito T, Taylor S, Li D, Moonen JR et al. 2021. Monocyte-released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition. JCI Insight 6:15e146416
     [Google Scholar]
  116. 116.
    Tang H, Babicheva A, McDermott KM, Gu Y, Ayon RJ et al. 2018. Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Am. J. Physiol. Lung Cell. Mol. Physiol. 314:L256–75
     [Google Scholar]
  117. 117.
    Glaser SF, Heumüller AW, Tombor L, Hofmann P, Muhly-Reinholz M et al. 2020. The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. PNAS 117:4180–87
     [Google Scholar]
  118. 118.
    Alonso-Herranz L, Sahun-Espanol A, Paredes A, Gonzalo P, Gkontra P et al. 2020. Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction. eLife 9:e57920
     [Google Scholar]
  119. 119.
    Noseda M, McLean G, Niessen K, Chang L, Pollet I et al. 2004. Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation. Circ. Res. 94:910–17
     [Google Scholar]
  120. 120.
    Xu X, Tan X, Tampe B, Nyamsuren G, Liu X et al. 2015. Epigenetic balance of aberrant Rasal1 promoter methylation and hydroxymethylation regulates cardiac fibrosis. Cardiovasc. Res. 105:279–91
     [Google Scholar]
  121. 121.
    Hong L, Li F, Tang C, Li L, Sun L et al. 2020. Semaphorin 7A promotes endothelial to mesenchymal transition through ATF3 mediated TGF-β2/Smad signaling. Cell Death Dis 11:695
     [Google Scholar]
  122. 122.
    Liu ZH, Zhang Y, Wang X, Fan XF, Zhang Y et al. 2019. SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition. Biomed. Pharmacother. 118:109227
     [Google Scholar]
  123. 123.
    Sanchez-Duffhues G, Garcia de Vinuesa A, van de Pol V, Geerts ME, de Vries MR et al. 2019. Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. J. Pathol. 247:333–46
     [Google Scholar]
  124. 124.
    Mammoto T, Muyleart M, Konduri GG, Mammoto A. 2018. Twist1 in hypoxia-induced pulmonary hypertension through transforming growth factor-β–Smad signaling. Am. J. Respir. Cell Mol. Biol. 58:194–207
     [Google Scholar]
  125. 125.
    Aisagbonhi O, Rai M, Ryzhov S, Atria N, Feoktistov I, Hatzopoulos AK. 2011. Experimental myocardial infarction triggers canonical Wnt signaling and endothelial-to-mesenchymal transition. Dis. Models Mech. 4:469–83
     [Google Scholar]
  126. 126.
    Ren Y, Zhang Y, Wang L, He F, Yan M et al. 2021. Selective targeting of vascular endothelial YAP activity blocks EndMT and ameliorates unilateral ureteral obstruction-induced kidney fibrosis. ACS Pharmacol. Transl. Sci. 4:1066–74
     [Google Scholar]
  127. 127.
    Savorani C, Malinverno M, Seccia R, Maderna C, Giannotta M et al. 2021. A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition. J. Cell Sci. 134:jcs251371
     [Google Scholar]
  128. 128.
    Tang H, Zhu M, Zhao G, Fu W, Shi Z et al. 2018. Loss of CLOCK under high glucose upregulates ROCK1-mediated endothelial to mesenchymal transition and aggravates plaque vulnerability. Atherosclerosis 275:58–67
     [Google Scholar]
  129. 129.
    Ahmed M, Zaghloul N, Zimmerman P, Casanova NG, Sun X et al. 2021. Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb. Pulm. Circ. 11:1–14
     [Google Scholar]
  130. 130.
    Li J, Liu H, Srivastava SP, Hu Q, Gao R et al. 2020. Endothelial FGFR1 (fibroblast growth factor receptor 1) deficiency contributes differential fibrogenic effects in kidney and heart of diabetic mice. Hypertension 76:1935–44
     [Google Scholar]
  131. 131.
    Liang X, Wu S, Geng Z, Liu L, Zhang S et al. 2021. LARP7 suppresses endothelial-to-mesenchymal transition by coupling with TRIM28. Circ. Res. 129:843–56
     [Google Scholar]
  132. 132.
    Wu B, Wang Y, Lui W, Langworthy M, Tompkins KL et al. 2011. Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation. Circ. Res. 109:183–92
     [Google Scholar]
  133. 133.
    Chen J, Jia J, Ma L, Li B, Qin Q et al. 2021. Nur77 deficiency exacerbates cardiac fibrosis after myocardial infarction by promoting endothelial-to-mesenchymal transition. J. Cell Physiol. 236:495–506
     [Google Scholar]
  134. 134.
    Huang N, Zhu TT, Liu T, Ge XY, Wang D et al. 2021. Aspirin ameliorates pulmonary vascular remodeling in pulmonary hypertension by dampening endothelial-to-mesenchymal transition. Eur. J. Pharmacol. 908:174307
     [Google Scholar]
  135. 135.
    Alkebsi L, Wang X, Ohkawara H, Fukatsu M, Mori H, Ikezoe T. 2021. Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib. Int. J. Hematol. 113:441–55
     [Google Scholar]
  136. 136.
    Jiang XH, Wu QQ, Xiao Y, Yuan Y, Yang Z et al. 2017. Evodiamine prevents isoproterenol-induced cardiac fibrosis by regulating endothelial-to-mesenchymal transition. Planta Med 83:761–69
     [Google Scholar]
  137. 137.
    Milan M, Pace V, Maiullari F, Chirivi M, Baci D et al. 2018. Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation. Cell Death Dis 9:108
     [Google Scholar]
  138. 138.
    Wu M, Peng Z, Zu C, Ma J, Lu S et al. 2016. Losartan attenuates myocardial endothelial-to-mesenchymal transition in spontaneous hypertensive rats via inhibiting TGF-β/Smad signaling. PLOS ONE 11:e0155730
     [Google Scholar]
  139. 139.
    Wei WY, Zhang N, Li LL, Ma ZG, Xu M et al. 2018. Pioglitazone alleviates cardiac fibrosis and inhibits endothelial to mesenchymal transition induced by pressure overload. Cell. Physiol. Biochem. 45:26–36
     [Google Scholar]
  140. 140.
    Jin YG, Yuan Y, Wu QQ, Zhang N, Fan D et al. 2017. Puerarin protects against cardiac fibrosis associated with the inhibition of TGF-β1/Smad2-mediated endothelial-to-mesenchymal transition. PPAR Res 2017:2647129
     [Google Scholar]
  141. 141.
    Zou J, Liu Y, Li B, Zheng Z, Ke X et al. 2017. Autophagy attenuates endothelial-to-mesenchymal transition by promoting Snail degradation in human cardiac microvascular endothelial cells. Biosci. Rep. 37:BSR20171049
     [Google Scholar]
  142. 142.
    Zhou X, Chen X, Cai JJ, Chen LZ, Gong YS et al. 2015. Relaxin inhibits cardiac fibrosis and endothelial-mesenchymal transition via the Notch pathway. Drug Des. Devel. Ther. 9:4599–611
     [Google Scholar]
  143. 143.
    Cai J, Chen X, Chen X, Chen L, Zheng G et al. 2017. Anti-fibrosis effect of relaxin and spironolactone combined on isoprenaline-induced myocardial fibrosis in rats via inhibition of endothelial-mesenchymal transition. Cell. Physiol. Biochem. 41:1167–78
     [Google Scholar]
  144. 144.
    Zhou H, Chen X, Chen L, Zhou X, Zheng G et al. 2014. Anti-fibrosis effect of scutellarin via inhibition of endothelial-mesenchymal transition on isoprenaline-induced myocardial fibrosis in rats. Molecules 19:15611–23
     [Google Scholar]
  145. 145.
    Tuuminen R, Syrjala S, Krebs R, Keranen MA, Koli K et al. 2011. Donor simvastatin treatment abolishes rat cardiac allograft ischemia/reperfusion injury and chronic rejection through microvascular protection. Circulation 124:1138–50
     [Google Scholar]
  146. 146.
    Wu Y, Xu M, Bao H, Zhang JH. 2019. Sitagliptin inhibits EndMT in vitro and improves cardiac function of diabetic rats through the SDF-1α/PKA pathway. Eur. Rev. Med. Pharmacol. Sci. 23:841–48
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-032222-080806
Loading
Endothelial to Mesenchymal Transition in Health and Disease
Annual Review of Physiology 85, 245 (2023); https://doi.org/10.1146/annurev-physiol-032222-080806
/content/journals/10.1146/annurev-physiol-032222-080806
/content/journals/10.1146/annurev-physiol-032222-080806
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error