Top

Published in:

Open Access 01-02-2019 | Review Paper

The therapeutic potential of targeting the endothelial-to-mesenchymal transition

Authors: Shirley Man, Gonzalo Sanchez Duffhues, Peter ten Dijke, David Baker

Published in: Angiogenesis | Issue 1/2019

Abstract

Endothelial cells (ECs) have been found to be capable of acquiring a mesenchymal phenotype through a process known as endothelial-to-mesenchymal transition (EndMT). First seen in the developing embryo, EndMT can be triggered postnatally under certain pathological conditions. During this process, ECs dedifferentiate into mesenchymal stem-like cells (MSCs) and subsequently give rise to cell types belonging to the mesoderm lineage. As EndMT contributes to a multitude of diseases, pharmacological modulation of the signaling pathways underlying EndMT may prove to be effective as a therapeutic treatment. Additionally, EndMT in ECs could also be exploited to acquire multipotent MSCs, which can be readily re-differentiated into various distinct cell types. In this review, we will consider current models of EndMT, how manipulation of this process might improve treatment of clinically important pathologies and how it could be harnessed to advance regenerative medicine and tissue engineering.

Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA (2009) Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119(6):1438–1449. https://doi.org/10.1172/JCI38019 CrossRefPubMedPubMedCentral

Kalluri R, Weinberg R (2009) Review series the basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428. https://doi.org/10.1172/JCI39104.1420 CrossRefPubMedPubMedCentral

Lim J, Thiery JP (2012) Epithelial-mesenchymal transitions: insights from development. Development 139(19):3471–3486. https://doi.org/10.1242/dev.071209 CrossRefPubMed

Kalluri R, Neilson EG (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112(12):1776–1784. https://doi.org/10.1172/JCI200320530 CrossRefPubMedPubMedCentral

Sanchez-Duffhues G, Orlova V, ten Dijke P (2016) In brief: endothelial-to-mesenchymal transition. J Pathol 238(3):378–380. https://doi.org/10.1002/path.4653 CrossRef

Medici D, Kalluri R (2012) Endothelial–mesenchymal transition and its contribution to the emergence of stem cell phenotype. Semin Cancer Biol 144(5):724–732. https://doi.org/10.1038/jid.2014.371 CrossRef

Welch-Reardon KM, Wu N, Hughes CCW (2015) A role for partial endothelial–mesenchymal transitions in angiogenesis? Arterioscler Thromb Vasc Biol 35(2):303–308. https://doi.org/10.1161/ATVBAHA.114.303220 CrossRefPubMed

Frid MG, Kale VA, Stenmark KR (2002) Mature vascular endothelium can give rise to smooth muscle cells via endothelialmesenchymal transdifferentiation: in vitro analysis. Circ Res 90(11):1189–1196. https://doi.org/10.1161/01.RES.0000021432.70309.28 CrossRefPubMed

Moonen JRAJ, Krenning G, Brinker MGL, Koerts JA, Van Luyn MJA, Harmsen MC (2010) Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny. Cardiovasc Res 86(3):506–515. https://doi.org/10.1093/cvr/cvq012 CrossRefPubMed

10.

Potenta S, Zeisberg E, Kalluri R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99(9):1375–1379. https://doi.org/10.1038/sj.bjc.6604662 CrossRefPubMedPubMedCentral

11.

Arciniegas E, Neves CY, Carrillo LM, Zambrano E, Ramírez R (2005) Endothelial–mesenchymal transition occurs during embryonic pulmonary artery development. Endothelium 12(4):193–200. https://doi.org/10.1080/10623320500227283 CrossRefPubMed

12.

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(14):1795–1808. https://doi.org/10.1161/CIRCULATIONAHA.111.040352 CrossRefPubMedPubMedCentral

13.

Armstrong EJ, Bischoff J (2004) Heart valve development: endothelial cell signaling and differentiation. Circ Res 95(5):459–470. https://doi.org/10.1161/01.RES.0000141146.95728.da CrossRefPubMedPubMedCentral

14.

Lin F, Wang N, Zhang TC (2012) The role of endothelial–mesenchymal transition in development and pathological process. IUBMB Life 64(9):717–723. https://doi.org/10.1002/iub.1059 CrossRefPubMed

15.

Ranchoux B, Antigny F, Rucker-Martin C et al (2015) Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131(11):1006–1018. https://doi.org/10.1161/CIRCULATIONAHA.114.008750 CrossRefPubMed

16.

Chen PY, Qin L, Baeyens N et al (2015) Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest 125(12):4514–4528. https://doi.org/10.1172/JCI82719 CrossRefPubMedPubMedCentral

17.

Piera-Velazquez S, Mendoza F, Jimenez S (2016) Endothelial to mesenchymal transition (EndoMT) in the pathogenesis of human fibrotic diseases. J Clin Med 5(4):45. https://doi.org/10.3390/jcm5040045 CrossRefPubMedCentral

18.

Kriz W, Kaissling B, Le Hir M (2011) Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J Clin Invest 121(2):468–474. https://doi.org/10.1172/JCI44595 CrossRefPubMedPubMedCentral

19.

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(12):1400–1406. https://doi.org/10.1038/nm.2252 CrossRefPubMedPubMedCentral

20.

Medici D (2016) Endothelial–mesenchymal transition in regenerative medicine. Stem Cells Int. https://doi.org/10.1155/2016/6962801 CrossRefPubMedPubMedCentral

21.

Guihard PJ, Yao J, Blazquez-medela AM, Iruela-arispe L (2016) Endothelial–mesenchymal transition in vascular calcification of Ins2 Akita/+ mice. PLoS ONE 11(12):1–12. https://doi.org/10.1371/journal.pone.0167936 CrossRef

22.

Evrard SM, Lecce L, Michelis KC et al (2016) Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat Commun. https://doi.org/10.1038/ncomms11853 CrossRefPubMedPubMedCentral

23.

van Meeteren LA, ten Dijke P (2011) Regulation of endothelial cell plasticity by TGF-β. Cell Tissue Res 347(1):177–186. https://doi.org/10.1007/s00441-011-1222-6 CrossRefPubMedPubMedCentral

24.

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(3):515–520. https://doi.org/10.1042/BJ20101500 CrossRefPubMed

25.

Gonzalez DM, Medici D (2014) Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 7(344):re8–re8. https://doi.org/10.1126/scisignal.2005189 CrossRefPubMedPubMedCentral

26.

27.

Piera-Velazquez S, Jimenez S (2012) Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases. Fibrogenesis Tissue Repair. 5 (Suppl 1 Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapiesPetro E Petrides and David Brenner):S7. https://doi.org/10.1186/1755-1536-5-S1-S7

28.

Li Z, Jimenez SA (2011) Protein kinase Cδ and c-Abl kinase are required for transforming growth factor β induction of endothelial–mesenchymal transition in vitro. Arthritis Rheum 63(8):2473–2483. https://doi.org/10.1002/art.30317 CrossRefPubMedPubMedCentral

29.

Cooley BC, Nevado J, Mellad J et al (2014) TGF-β signaling mediates endothelial to mesenchymal transition (EndMT) during vein graft remodeling. Sci Trans Med 6(227):1–22. https://doi.org/10.1126/scitranslmed.3006927.TGF- CrossRef

30.

Xavier S, Vasko R, Matsumoto K et al (2015) Curtailing endothelial TGF-β signaling is sufficient to reduce endothelial–mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol 26(4):817–829. https://doi.org/10.1681/ASN.2013101137 CrossRefPubMed

31.

Clevers H, Nusse R (2012) Wnt/β-catenin signaling and disease. Cell 149(6):1192–1205. https://doi.org/10.1016/j.cell.2012.05.012 CrossRefPubMed

32.

Liebner S, Cattelino A, Gallini R et al (2004) β-catenin is required for endothelial–mesenchymal transformation during heart cushion development in the mouse. J Cell Biol 166(3):359–367. https://doi.org/10.1083/jcb.200403050 CrossRefPubMedPubMedCentral

33.

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 Model Mech 4(4):469–483. https://doi.org/10.1242/dmm.006510 CrossRefPubMedPubMedCentral

34.

Beyer C, Schramm A, Akhmetshina A et al (2012) β-catenin is a central mediator of pro-fibrotic Wnt signaling in systemic sclerosis. Ann Rheum Dis 71(5):761–767. https://doi.org/10.1136/annrheumdis-2011-200568 CrossRefPubMed

35.

Li L, Chen L, Zang J 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(5):597–610. https://doi.org/10.1016/j.metabol.2015.01.014 CrossRefPubMed

36.

Wang S-H, Chang JS, Hsiao J-R et al (2016) Tumour cell-derived WNT5B modulates in vitro lymphangiogenesis via induction of partial endothelial–mesenchymal transition of lymphatic endothelial cells. Oncogene 36(April):1–13. https://doi.org/10.1038/onc.2016.317 CrossRef

37.

Noseda M, McLean G, Niessen K et al (2004) Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation. Circ Res 94(7):910–917. https://doi.org/10.1161/01.RES.0000124300.76171.C9 CrossRefPubMed

38.

Chang ACY, Fu Y, Garside VC et al (2011) Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase. Dev Cell 21(2):288–300. https://doi.org/10.1016/j.devcel.2011.06.022 CrossRefPubMed

39.

Fu Y, Chang A, Chang L et al (2009) Differential regulation of transforming growth factor β signaling pathways by Notch in human endothelial cells. J Biol Chem 284(29):19452–19462. https://doi.org/10.1074/jbc.M109.011833 CrossRefPubMedPubMedCentral

40.

Gasperini P, Espigol-Frigole G, McCormick PJ et al (2012) Kaposi sarcoma herpesvirus promotes endothelial-to-mesenchymal transition through notch-dependent signaling. Cancer Res 72(5):1157–1169. https://doi.org/10.1158/0008-5472.CAN-11-3067 CrossRefPubMedPubMedCentral

41.

Del Galdo F, Lisanti MP, Jimenez SA (2008) Caveolin-1, transforming growth factor-β receptor internalization, and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 20(6):713–719CrossRefPubMedPubMedCentral

42.

Li Z, Wermuth PJ, Benn BS, Lisanti MP, Jimenez SA (2013) Caveolin-1 deficiency induces spontaneous endothelial-to-mesenchymal transition in murine pulmonary endothelial cells in vitro. Am J Pathol 182(2):325–331. https://doi.org/10.1016/j.ajpath.2012.10.022 CrossRefPubMedPubMedCentral

43.

Widyantoro B, Emoto N, Nakayama K et al (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121(22):2407–2418. https://doi.org/10.1161/CIRCULATIONAHA.110.938217 CrossRefPubMed

44.

Wermuth PJ, Li Z, Mendoza FA, Jimenez SA. Stimulation of transforming growth factor-β1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1 (ET-1): A novel profibrotic effect of ET-1. PLoS ONE. 2016;11(9). https://doi.org/10.1371/journal.pone.0161988

45.

Cipriani P, Di Benedetto P, Ruscitti P et al (2015) The endothelial–mesenchymal transition in systemic sclerosis is induced by endothelin-1 and transforming growth factor-β and may be blocked by Macitentan, a dual endothelin-1 receptor antagonist. J Rheumatol 42(10):1808–1816. https://doi.org/10.3899/jrheum.150088 CrossRefPubMed

46.

Rieder F, Kessler SP, West GA et al (2011) Inflammation-induced endothelial-to-mesenchymal transition: a novel mechanism of intestinal fibrosis. Am J Pathol 179(5):2660–2673. https://doi.org/10.1016/j.ajpath.2011.07.042 CrossRefPubMedPubMedCentral

47.

Mahler GJ, Farrar EJ, Butcher JT (2013) Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. Arterioscler Thromb Vasc Biol 33(1):121–130. https://doi.org/10.1161/ATVBAHA.112.300504 CrossRefPubMed

48.

Chrobak I, Lenna S, Stawski L, Trojanowska M (2013) Interferon-γ promotes vascular remodeling in human microvascular endothelial cells by upregulating endothelin (ET)-1 and transforming growth factor (TGF) β2. J Cell Physiol 228(8):1774–1783. https://doi.org/10.1002/jcp.24337 CrossRefPubMedPubMedCentral

49.

Parks WC, Parks WC, Wilson CL, Wilson CL, López-Boado YS, López-Boado YS (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. https://doi.org/10.1038/nri1418 CrossRefPubMed

50.

Ho WT, Chang JS, Su CC et al (2015) Inhibition of matrix metalloproteinase activity reverses corneal endothelial–mesenchymal transition. Am J Pathol 185(8):2158–2167. https://doi.org/10.1016/j.ajpath.2015.04.005 CrossRefPubMed

51.

Zhao Y, Qiao X, Wang L et al (2016) Matrix metalloproteinase 9 induces endothelial–mesenchymal transition via Notch activation in human kidney glomerular endothelial cells. BMC Cell Biol. https://doi.org/10.1186/s12860-016-0101-0 CrossRefPubMedPubMedCentral

52.

Xu X, Tan X, Tampe B, Sanchez E, Zeisberg M, Zeisberg EM (2015) Snail Is a direct target of hypoxia-inducible factor 1α (HIF1α) in hypoxia-induced endothelial to mesenchymal transition of human coronary endothelial cells. J Biol Chem 290(27):16553–16664. https://doi.org/10.1074/jbc.M115.636944 CrossRef

53.

Choi SH, Hong ZY, Nam JK et al (2015) A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis. Clin Cancer Res 21(16):3716–3726. https://doi.org/10.1158/1078-0432.CCR-14-3193 CrossRefPubMed

54.

Song S, Zhang M, Yi Z et al (2016) The role of PDGF-B/TGF-β1/neprilysin network in regulating endothelial-to-mesenchymal transition in pulmonary artery remodeling. Cell Signal 28(10):1489–1501. https://doi.org/10.1016/j.cellsig.2016.06.022 CrossRefPubMed

55.

Liu R-M, Gaston Pravia KA (2010) Oxidative stress and glutathione in TGF-β-mediated fibrogenesis. Free Radic Biol Med 48(1):1–15. https://doi.org/10.1016/j.freeradbiomed.2009.09.026 CrossRefPubMed

56.

Maleszewska M, Moonen J-RAJ, Huijkman N, van de Sluis B, Krenning G, Harmsen MC (2013) IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner. Immunobiology 218(4):443–454. https://doi.org/10.1016/j.imbio.2012.05.026 CrossRefPubMed

57.

Amara N, Goven D, Prost F, Muloway R, Crestani B, Boczkowski J (2010) NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFβ1-induced fibroblast differentiation into myofibroblasts. Thorax 65(8):733–738. https://doi.org/10.1136/thx.2009.113456 CrossRefPubMed

58.

Liu RM, Desai LP (2015) Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol 6:565–577. https://doi.org/10.1016/j.redox.2015.09.009 CrossRefPubMedPubMedCentral

59.

Wang Z, Han Z, Tao J et al. (2017) Role of endothelial-to-mesenchymal transition induced by TGF-β1 in transplant kidney interstitial fibrosis. J Cell Mol Med 21(10): 2359–2369

60.

Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10(1):53–62. https://doi.org/10.1038/nrm2596 CrossRefPubMedPubMedCentral

61.

Krenning G, Barauna VG, Krieger JE, Harmsen MC, Moonen JRAJ (2016) Endothelial plasticity: shifting phenotypes through force feedback. Stem Cells Int. https://doi.org/10.1155/2016/9762959 CrossRefPubMedPubMedCentral

62.

Moonen JRAJ, Lee ES, Schmidt M et al (2015) Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress. Cardiovasc Res 108(3):377–386. https://doi.org/10.1093/cvr/cvv175 CrossRefPubMed

63.

Balachandran K, Alford PW, Wylie-Sears J et al (2011) Cyclic strain induces dual-mode endothelial–mesenchymal transformation of the cardiac valve. Proc Natl Acad Sci 108(50):19943–19948. https://doi.org/10.1073/pnas.1106954108 CrossRefPubMedPubMedCentral

64.

Mai J, Hu Q, Xie Y et al (2014) Dyssynchronous pacing triggers endothelial–mesenchymal transition through heterogeneity of mechanical stretch in a canine model. Circ J 79(1):201–209. https://doi.org/10.1253/circj.CJ-14-0721 CrossRefPubMed

65.

Nagpal V, Rai R, Place AT et al (2016) MiR-125b is critical for fibroblast-to-myofibroblast transition and cardiac fibrosis. Circulation 133(3):291–301. https://doi.org/10.1161/CIRCULATIONAHA.115.018174 CrossRefPubMed

66.

Kumarswamy R, Volkmann I, Jazbutyte V, Dangwal S, Park DH, Thum T (2012) Transforming growth factor-β-induced endothelial-to-mesenchymal transition is partly mediated by MicroRNA-21. Arterioscler Thromb Vasc Biol 32(2):361–369. https://doi.org/10.1161/ATVBAHA.111.234286 CrossRefPubMed

67.

Katsura A, Suzuki HI, Ueno T et al (2016) MicroRNA-31 is a positive modulator of endothelial–mesenchymal transition and associated secretory phenotype induced by TGF-β Genes Cells 21(1):99–116. https://doi.org/10.1111/gtc.12323 CrossRefPubMed

68.

Chakraborty S, Zawieja DC, Davis MJ, Muthuchamy M (2015) MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation. Am J Physiol Cell Physiol 309(10):C680–C692. https://doi.org/10.1152/ajpcell.00122.2015 CrossRefPubMedPubMedCentral

69.

Xiang Y, Zhang Y, Tang Y, Li Q (2017) MALAT1 modulates TGF-β1-induced endothelial-to-mesenchymal transition through downregulation of miR-145. Cell Physiol Biochem 42(1):357–372. https://doi.org/10.1159/000477479 CrossRefPubMed

70.

Goumans MJ, Valdimarsdottir G, Itoh S et al (2003) Activin receptor-like kinase (ALK) 1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol Cell 12:817–828. https://doi.org/10.1016/S1097-2765(03)00386-1 CrossRefPubMed

71.

Lebrin F, Goumans M-J, Jonker L et al (2004) Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J 23(20):4018–4028. https://doi.org/10.1038/sj.emboj.7600386 CrossRefPubMedPubMedCentral

72.

Zeisberg EM, Tarnavski O, Zeisberg M et al (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13(8):952–961. https://doi.org/10.1038/nm1613 CrossRefPubMed

73.

Paruchuri S, Yang J, Aikawa E 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(8):861–869. https://doi.org/10.1161/01.RES.0000245188.41002.2c CrossRefPubMedPubMedCentral

74.

Tao J, Doughman Y, Yang K, Ramirez-Bergeron D, Watanabe M (2013) Epicardial HIF signaling regulates vascular precursor cell invasion into the myocardium. Dev Biol 376(2):136–149. https://doi.org/10.1016/j.ydbio.2013.01.026 CrossRefPubMedPubMedCentral

75.

Bai Y, Wang J, Morikawa Y, Bonilla-Claudio M, Klysik E, Martin JF (2013) Bmp signaling represses Vegfa to promote outflow tract cushion development. Development 140(16):3395–3402. https://doi.org/10.1242/dev.097360 CrossRefPubMedPubMedCentral

76.

Ying R, Wang XQ, Yang Y et al (2016) Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway. Life Sci 144:208–217. https://doi.org/10.1016/j.lfs.2015.11.025 CrossRefPubMed

77.

Yan F, Zhang G-H, Feng M et al (2015) Glucagon-like peptide 1 protects against hyperglycemic-induced endothelial-to-mesenchymal transition and improves myocardial dysfunction by suppressing poly (ADP-ribose) polymerase 1 activity. Mol Med 21:15–25. https://doi.org/10.2119/molmed.2014.00259 CrossRefPubMedPubMedCentral

78.

Spillmann F, Miteva K, Pieske B, Tschöpe C, Van Linthout S (2015) High-density lipoproteins reduce endothelial-to-mesenchymal transition. Arterioscler Thromb Vasc Biol 35(8):1774–1777. https://doi.org/10.1161/ATVBAHA.115.305887 CrossRefPubMed

79.

Choi SH, Nam JK, Kim BY et al (2016) HSPB1 inhibits the endothelial-to-mesenchymal transition to suppress pulmonary fibrosis and lung tumorigenesis. Cancer Res 76(5):1019–1030. https://doi.org/10.1158/0008-5472.CAN-15-0952 CrossRefPubMed

80.

Bai J, Hao J, Zhang X, Cui H, Han J, 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(1):47. https://doi.org/10.1186/s12882-016-0260-4 CrossRefPubMedPubMedCentral

81.

Harikrishnan K, Cooley MA, Sugi Y et al (2015) Fibulin-1 suppresses endothelial to mesenchymal transition in the proximal outflow tract. Mech Dev 136:123–132. https://doi.org/10.1016/j.mod.2014.12.005 CrossRefPubMedPubMedCentral

82.

Zordan P, Rigamonti E, Freudenberg K et al (2014) Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. Cell Death Dis 5(1):e1031. https://doi.org/10.1038/cddis.2013.558 CrossRefPubMedPubMedCentral

83.

Bonet F, Dueñas Á, López-Sánchez C, García-Martínez V, Aránega AE, Franco D (2015) MiR-23b and miR-199a impair epithelial-to-mesenchymal transition during atrioventricular endocardial cushion formation. Dev Dyn 244(10):1259–1275. https://doi.org/10.1002/dvdy.24309 CrossRefPubMed

84.

Zhang J, Zhang Z, Zhang DY, Zhu J, Zhang T, Wang C (2013) MicroRNA 126 inhibits the transition of endothelial progenitor cells to mesenchymal cells via the PIK3R2-PI3K/Akt signalling pathway. PLoS ONE. 8(12). https://doi.org/10.1371/journal.pone.0083294

85.

Kumar S, Kim CW, Simmons RD, Jo H (2014) Role of flow-sensitive microRNAs in endothelial dysfunction and atherosclerosis mechanosensitive athero-miRs. Arterioscler Thromb Vasc Biol 34(10):2206–2216. https://doi.org/10.1161/ATVBAHA.114.303425 CrossRefPubMedPubMedCentral

86.

Bijkerk R, de Bruin RG, van Solingen C et al (2012) MicroRNA-155 functions as a negative regulator of RhoA signaling in TGF-β-induced endothelial to mesenchymal transition. MicroRNA (Shariqah United Arab Emirates) 1(1):2–10. https://doi.org/10.2174/2211536611201010002 CrossRef

87.

Zhu K, Pan Q, Jia L-Q et al (2014) MiR-302c inhibits tumor growth of hepatocellular carcinoma by suppressing the endothelial–mesenchymal transition of endothelial cells. Sci Rep 4:5524. https://doi.org/10.1038/srep05524 CrossRefPubMedPubMedCentral

88.

Chen PY, Qin L, Barnes C et al (2012) FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. Cell Rep 2(6):1684–1696. https://doi.org/10.1016/j.celrep.2012.10.021 CrossRefPubMedPubMedCentral

89.

Nagai T, Kanasaki M, Srivastava SP et al. (2014) N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial–mesenchymal transition. Biomed Res Int. https://doi.org/10.1155/2014/696475 CrossRefPubMedPubMedCentral

90.

Lee JG, Ko MK, Kay EP (2012) Endothelial mesenchymal transformation mediated by IL-1β-induced FGF-2 in corneal endothelial cells. Exp Eye Res 95(1):35–39. https://doi.org/10.1016/j.exer.2011.08.003 CrossRefPubMed

91.

Correia ACP, Moonen J-RAJ, Brinker MGL, Krenning G (2016) FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling. J Cell Sci 129(3):569–579. https://doi.org/10.1242/jcs.176248 CrossRefPubMed

92.

Sun Y, Cai J, Yu S, Chen S, Li F, Fan C (2016) MiR-630 inhibits endothelial–mesenchymal transition by targeting slug in traumatic heterotopic ossification. Sci Rep 6:22729. https://doi.org/10.1038/srep22729 CrossRefPubMedPubMedCentral

93.

Grassi G, Di Caprio G, Santangelo L et al (2015) Autophagy regulates hepatocyte identity and epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions promoting Snail degradation. Cell Death Dis 6(9):e1880. https://doi.org/10.1038/cddis.2015.249 CrossRefPubMedPubMedCentral

94.

Wang J, Feng Y, Wang Y, Xiang D, Zhang X, Yuan F (2017) Autophagy regulates endothelial–mesenchymal transition by decreasing the phosphorylation level of Smad3. Biochem Biophys Res Commun 487(3):740–747. https://doi.org/10.1016/j.bbrc.2017.04.130 CrossRefPubMed

95.

Marchi S, Trapani E, Corricelli M, Goitre L, Pinton P, Retta SF (2016) Beyond multiple mechanisms and unique drugs: defective autophagy as pivotal player in cerebral cavernous malformation pathogenesis and implications for targeted therapies. Rare Dis 5511(May):00–00. https://doi.org/10.1080/21675511.2016.1142640 CrossRef

96.

Boyer AS, Ayerinskas II, Vincent EB, McKinney LA, Weeks DL, Runyan RB (1999) TGFβ2 and TGFβ3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Biol 208(2):530–545. https://doi.org/10.1006/dbio.1999.9211 CrossRefPubMed

97.

Mercado-Pimentel ME, Runyan RB (2007) Multiple transforming growth factor-β isoforms and receptors function during epithelial-mesenchymal cell transformation in the embryonic heart. Cells Tissues Organs 185:146–156. https://doi.org/10.1159/000101315 CrossRef

98.

Sridurongrit S, Larsson J, Schwartz R, Ruiz-Lozano P, Kaartinen V (2008) Signaling via the Tgf-β type I receptor Alk5 in heart development. Dev Biol 322(1):208–218. https://doi.org/10.1016/j.ydbio.2008.07.038 CrossRefPubMedPubMedCentral

99.

Agarwal S, Loder S, Cholok D et al (2016) Local and circulating endothelial cells undergo endothelial to mesenchymal transition (EndMT) in response to musculoskeletal injury. Sci Rep 6:32514. https://doi.org/10.1038/srep32514 CrossRefPubMedPubMedCentral

100.

Shi S, Srivastava SP, Kanasaki M et al (2015) Interactions of DPP-4 and integrin β1 influences endothelial-to-mesenchymal transition. Kidney Int 88(3):479–489. https://doi.org/10.1038/ki.2015.103 CrossRefPubMed

101.

Bianchini F, Peppicelli S, Fabbrizzi P et al (2017) Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells. Mol Cell Biochem 424(1–2):99–110. https://doi.org/10.1007/s11010-016-2847-2 CrossRefPubMed

102.

Li J, Qu X, Yao J et al. (2010) Blockade of endothelial–mesenchymal transition by a smad3 inhibitor delays the early development of streptozotocin-induced diabetic nephropathy. 59. https://doi.org/10.2337/db09-1631

103.

Gong F, Zhao F, Gan X.(2017) Celastrol protects TGF- β 1-induced endothelial–mesenchymal transition. 37(2):185–190. https://doi.org/10.1007/s11596-017-1713-0

104.

Guo Y, Li P, Bledsoe G, Yang ZR, Chao L, Chao J (2015) Kallistatin inhibits TGF-β-induced endothelial–mesenchymal transition by differential regulation of microRNA-21 and eNOS expression. Exp Cell Res 337(1):103–110. https://doi.org/10.1016/j.yexcr.2015.06.021 CrossRefPubMedPubMedCentral

105.

Wylie-Sears J, Levine RA, Bischoff J (2014) Losartan inhibits endothelial-to-mesenchymal transformation in mitral valve endothelial cells by blocking transforming growth factor-β-induced phosphorylation of ERK. Biochem Biophys Res Commun 446(4):870–875. https://doi.org/10.1016/j.bbrc.2014.03.014 CrossRefPubMedPubMedCentral

106.

Chen X, Cai J, Zhou X et al (2015) Protective effect of spironolactone on endothelial-to-mesenchymal transition in HUVECS via notch pathway. Cell Physiol Biochem 36(1):191–200. https://doi.org/10.1159/000374063 CrossRefPubMed

107.

Zhou H, Chen X, Chen L et al (2014) Anti-fibrosis effect of scutellarin via inhibition of endothelial–mesenchymal transition on isoprenaline-induced myocardial fibrosis in rats. Molecules 19(10):15611–15623. https://doi.org/10.3390/molecules191015611 CrossRefPubMedPubMedCentral

108.

Corallo C, Cutolo M, Kahaleh B et al (2016) Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study. Arthritis Res Ther 18(1):228. https://doi.org/10.1186/s13075-016-1122-y CrossRefPubMedPubMedCentral

109.

Gao H, Zhang J, Liu T, Shi W (2011) Rapamycin prevents endothelial cell migration by inhibiting the endothelial-to-mesenchymal transition and matrix metalloproteinase-2 and -9: an in vitro study. Mol Vis 17(12):3406–3414.PubMedPubMedCentral

110.

Zhou X, Chen X, Cai JJ et al (2015) Relaxin inhibits cardiac fibrosis and endothelial–mesenchymal transition via the Notch pathway. Drug Des Devel Ther 9:4599–4611. https://doi.org/10.2147/DDDT.S85399 CrossRefPubMedPubMedCentral

111.

Bravi L, Rudini N, Cuttano R et al (2015) Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. Proc Natl Acad Sci 112(27):8421–8426. https://doi.org/10.1073/pnas.1501352112 CrossRefPubMedPubMedCentral

112.

wu M, Tang R, Liu H, Pan M, Liu B (2016) Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition. Nat Publ Gr 37(11):1–9. https://doi.org/10.1038/aps.2016.83 CrossRef

113.

Deng Y, Guo Y, Liu P et al (2016) Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy. Sci Rep 6(1):19821. https://doi.org/10.1038/srep19821 CrossRefPubMedPubMedCentral

114.

Furihata T, Kawamatsu S, Ito R et al (2015) Hydrocortisone enhances the barrier properties of HBMEC/ciβ, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS 12(1):1–15. https://doi.org/10.1186/s12987-015-0003-0 CrossRef

115.

Qi Q, Mao Y, Tian Y et al (2017) Geniposide inhibited endothelial–mesenchymal transition via the mTOR signaling pathway in a bleomycin-induced scleroderma mouse model. Am J Transl Res 9(3):1025–1036PubMedPubMedCentral

116.

Shore EM, Xu M, Feldman GJ et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527. https://doi.org/10.1038/ng1783 CrossRefPubMed

117.

Lounev VY, Ramachandran R, Wosczyna MN et al (2009) Identification of progenitor cells that contribute to heterotopic identification of progenitor cells that contribute to heterotopic skeletogenesis. J Bone Joint Surg Am 91(3):652–663. https://doi.org/10.2106/JBJS.H.01177 CrossRefPubMedPubMedCentral

118.

Yao J, Guihard PJ, Blazquez-Medela AM et al (2015) Serine protease activation essential for endothelial–mesenchymal transition in vascular calcification. Circ Res 117(9):758–769. https://doi.org/10.1161/CIRCRESAHA.115.306751 CrossRefPubMedPubMedCentral

119.

Hjortnaes J, Shapero K, Goettsch C et al (2015) Valvular interstitial cells suppress calcification of valvular endothelial cells. Atherosclerosis 242(1):251–260. https://doi.org/10.1016/j.atherosclerosis.2015.07.008 CrossRefPubMedPubMedCentral

120.

Dudley AC, Khan ZA, Shih SC et al (2008) Calcification of multipotent prostate tumor endothelium. Cancer Cell 14(3):201–211. https://doi.org/10.1016/j.ccr.2008.06.017 CrossRefPubMedPubMedCentral

121.

Tang R, Wu M, Gao M, Liu H, Zhang X, Liu B (2012) High glucose mediates endothelial-to-chondrocyte transition in human aortic endothelial cells. Cardiovasc Diabetol 11(1):113. https://doi.org/10.1186/1475-2840-11-113 CrossRefPubMedPubMedCentral

122.

Tran K-V, Gealekman O, Frontini A et al (2012) The vascular endothelium of the adipose tissue gives rise to both white and brown fat cells. Cell Metab 15(2):222–229. https://doi.org/10.1016/j.cmet.2012.01.008 CrossRefPubMedPubMedCentral

123.

Huang L, Nakayama H, Klagsbrun M, Mulliken JB, Bischoff J (2015) Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells 33(1):133–145. https://doi.org/10.1002/stem.1841 CrossRefPubMedPubMedCentral

124.

Huang P, Schulz TJ, Beauvais A, Tseng Y-H, Gussoni E (2014) Intramuscular adipogenesis is inhibited by myo-endothelial progenitors with functioning Bmpr1a signalling. Nat Commun 5:4063. https://doi.org/10.1038/ncomms5063 CrossRefPubMed

125.

Fioret BA, Heimfeld JD, Paik DT, Hatzopoulos AK (2014) Endothelial cells contribute to generation of adult ventricular myocytes during cardiac homeostasis. Cell Rep 8(1):229–241. https://doi.org/10.1016/j.celrep.2014.06.004 CrossRefPubMedPubMedCentral

126.

Welch-Reardon KM, Ehsan SM, Wang K et al (2014) Angiogenic sprouting is regulated by endothelial cell expression of Slug. J Cell Sci 127(Pt 9):2017–2028. https://doi.org/10.1242/jcs.143420 CrossRefPubMedPubMedCentral

127.

Zhang W, Chen G, Ren JG, Zhao YF (2013) Bleomycin induces endothelial mesenchymal transition through activation of mTOR pathway: A possible mechanism contributing to the sclerotherapy of venous malformations. Br J Pharmacol 170(6):1210–1220. https://doi.org/10.1111/bph.12355 CrossRefPubMedPubMedCentral

128.

Muylaert DEP, de Jong OG, Slaats GGG et al (2015) Environmental influences on endothelial to mesenchymal transition in developing implanted cardiovascular tissue-engineered grafts. Tissue Eng Part B Rev 22(1):58–67. https://doi.org/10.1089/ten.teb.2015.0167 CrossRefPubMed

129.

Reichman D, Man L, Park L et al (2016) Notch hyper-activation drives trans-differentiation of hESC-derived endothelium. Stem Cell Res 17(2):391–400. https://doi.org/10.1016/j.scr.2016.09.005 CrossRefPubMed

130.

Hahn S, Nam M-O, Noh JH et al (2017) Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective. Sci Rep 7(1):2435. https://doi.org/10.1038/s41598-017-02190-5 CrossRefPubMedPubMedCentral

131.

Ibrahim M, Richardson MK (2017) Beyond organoids: in vitro vasculogenesis and angiogenesis using cells from mammals and zebrafish. Reprod Toxicol. https://doi.org/10.1016/j.reprotox.2017.07.002 CrossRefPubMed

Title: The therapeutic potential of targeting the endothelial-to-mesenchymal transition
Authors: Shirley Man
Gonzalo Sanchez Duffhues
Peter ten Dijke
David Baker
Publication date: 01-02-2019
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 1/2019
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-018-9639-0

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

The therapeutic potential of targeting the endothelial-to-mesenchymal transition

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2019

Understanding the evolving phenotype of vascular complications in telomere biology disorders

Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation

Cellular self-assembly into 3D microtissues enhances the angiogenic activity and functional neovascularization capacity of human cardiopoietic stem cells

Extracellular vesicles of multiple myeloma cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogenesis

Perfused 3D angiogenic sprouting in a high-throughput in vitro platform

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page