{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:40:12Z","timestamp":1790505612037,"version":"4.1.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"sichuan science and technology program","award":["2018JY0406\/2019YFS0537\/2020YFS0456"],"award-info":[{"award-number":["2018JY0406\/2019YFS0537\/2020YFS0456"]}]},{"DOI":"10.13039\/501100001809","name":"the natural science foundation of china","doi-asserted-by":"crossref","award":["81970676"],"award-info":[{"award-number":["81970676"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>The aim of this research was to systematically investigate the effects of endothelial mesenchymal transition (EndMT) induced by hypoxia on the skin microvascular remodeling of systemic sclerosis (SSc) and the underlying mechanism.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Skin tissues from SSc patients and controls were collected for isobaric tags for the relative and absolute quantification (iTRAQ)-based proteomics and immunohistochemical test. Human microvascular endothelial cell line-1 (HMEC-1) cultured in hypoxic or normal conditions was treated by tamoxifen or bevacizumab.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The iTRAQ-based proteomics indicated a significantly upregulated hypoxia-inducible factor-1 (HIF-1) signal in SSc samples. The immunohistochemical results demonstrated the significant downregulation of CD31, the positive staining of \u03b1-smooth muscle actin (\u03b1-SMA), HIF-1\u03b1, and vascular endothelial growth factor (VEGF-a) in SSc skin tissues, compared with control samples. Consistent with these observations, HMEC-1 cells cultured under hypoxic conditions exhibited a significant decrease in CD31 and VE-cadherin expression, alongside a marked increase in the expression of \u03b1-SMA and fibronectin, as well as a distinct upregulation of HIF-1\u03b1 and VEGF-a, when compared with those under normal conditions. It is noteworthy that the inhibition of HIF-1\u03b1 by tamoxifen effectively downregulated the hypoxic induction of VEGF-a and \u03b1-SMA while rescuing the hypoxic suppression of CD31. In addition, the VEGF-a inhibitor bevacizumab treatment had the same effect on the hypoxic expression of \u03b1-SMA and CD31, as a tamoxifen intervention, but did not reduce HIF-1\u03b1.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>These results suggest that the HIF-1\u03b1\/VEGF signaling pathway can have a critical role in mediating the effect of hypoxia-induced EndMT on the skin microvascular remodeling of SSc.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0263369","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T18:37:56Z","timestamp":1646159876000},"page":"e0263369","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Hypoxia-induced interstitial transformation of microvascular endothelial cells by mediating HIF-1\u03b1\/VEGF signaling in systemic sclerosis"],"prefix":"10.1371","volume":"17","author":[{"given":"Jing","family":"Mao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexiong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiqiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2023-830X","authenticated-orcid":true,"given":"Yongqiong","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,3,1]]},"reference":[{"key":"pone.0263369.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/4636859","article-title":"Vascular Remodelling and Mesenchymal Transition in Systemic Sclerosis","volume":"2016","author":"PA Nicolosi","year":"2016","journal-title":"Stem Cells Int"},{"issue":"7","key":"pone.0263369.ref002","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1080\/1744666X.2019.1614915","article-title":"Pathophysiology of systemic sclerosis: current understanding and new insights","volume":"15","author":"Cutolo Maurizio","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"pone.0263369.ref003","first-page":"733","article-title":"Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis","volume":"22","author":"M Beon","year":"2004","journal-title":"Clin. 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Snail Is a Direct Target of Hypoxia-inducible Factor 1\u03b1 (HIF1\u03b1) in Hypoxia-induced Endothelial to Mesenchymal Transition of Human Coronary Endothelial Cells","volume":"290","author":"Xu Xingbo","year":"2015","journal-title":"J. Biol. Chem"},{"key":"pone.0263369.ref012","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.cellimm.2016.04.001","article-title":"Hypoxia-inducible factor 1 in autoimmune diseases","volume":"303","author":"Deng Wei","year":"2016","journal-title":"Cell. 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Pharmacol"},{"key":"pone.0263369.ref015","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative","volume":"72","author":"Frank van den Hoogen","year":"2013","journal-title":"Ann. Rheum. Dis"},{"key":"pone.0263369.ref016","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1111\/ceo.13579","article-title":"Gillies Mark C. Effects of VEGF inhibitors on human retinal pigment epithelium under high glucose and hypoxia","volume":"47","author":"Bahrami Bobak","year":"2019","journal-title":"Clin. Experiment. Ophthalmol"},{"key":"pone.0263369.ref017","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.5152\/eurjrheum.2019.19158","article-title":"Endothelial cells\u2002and\u2002endothelial progenitor cells\u2002in the\u2002pathogenesis\u2002of\u2002systemic sclerosis","volume":"7","author":"Y Ota","year":"2020","journal-title":"Eur J Rheumatol"},{"issue":"4","key":"pone.0263369.ref018","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/s41584-020-0386-4","article-title":"Raynaud Phenomenon and Digital Ulcers in Systemic Sclerosis","volume":"16","author":"Michael Hughes","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"pone.0263369.ref019","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"C. P. Denton","year":"2017","journal-title":"Lancet"},{"key":"pone.0263369.ref020","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1136\/annrheumdis-2011-200742","article-title":"Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database","volume":"71","author":"M P Meier Florian","year":"2012","journal-title":"Ann. Rheum. Dis"},{"key":"pone.0263369.ref021","first-page":"1285","article-title":"Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database","volume":"75","author":"G Wirz Elina","year":"2015","journal-title":"Ann. Rheum. Dis"},{"key":"pone.0263369.ref022","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.5152\/eurjrheum.2019.19081","article-title":"Manetti M1. The contribution of mesenchymal transitions to the pathogenesis of systemic sclerosis","volume":"7","author":"I Rosa","year":"2020","journal-title":"Eur J Rheumatol"},{"key":"pone.0263369.ref023","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1002\/art.30316","article-title":"The origin of the myo fibroblast in fibroproliferative vasculopathy: does the endothelial cell steer the pathophysiology of systemic sclerosis?","volume":"63","author":"M Manetti","year":"2011","journal-title":"Arthritis Rheum"},{"key":"pone.0263369.ref024","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1126\/science.1066373","article-title":"A conserved family of prolyl-4-hydroxylases that modify HIF","volume":"294","author":"RK Bruick","year":"2001","journal-title":"Science"},{"key":"pone.0263369.ref025","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1124\/mol.106.027029","article-title":"Hypoxia-inducible factor-1 (HIF-1)","volume":"70","author":"Q Ke","year":"2006","journal-title":"Mol Pharmacol"},{"key":"pone.0263369.ref026","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.3892\/etm.2016.3782","article-title":"Acroosteolysis in systemic sclerosis: An insight into hypoxia-related pathogenesis","volume":"12","author":"Laura-Otilia Damian Simon Siao-Pin","year":"2016","journal-title":"Exp Ther Med"},{"key":"pone.0263369.ref027","doi-asserted-by":"crossref","first-page":"13459","DOI":"10.1073\/pnas.192342099","article-title":"Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor","volume":"99","author":"Ivan Mircea","year":"2002","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"pone.0263369.ref028","doi-asserted-by":"crossref","first-page":"824972","DOI":"10.1155\/2011\/824972","article-title":"A system out of breath: how hypoxia possibly contributes to the pathogenesis of systemic sclerosis","volume":"2011","author":"T W van Hal","year":"2011","journal-title":"Int J Rheumatol"},{"key":"pone.0263369.ref029","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-inducible factors in physiology and medicine","volume":"148","author":"GL Semenza","year":"2012","journal-title":"Cell"},{"key":"pone.0263369.ref030","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/B978-0-12-394307-1.00003-5","article-title":"Hypoxia and hypoxia signaling in tissue repair and fibrosis","volume":"296","author":"Z Lokmic","year":"2012","journal-title":"Int Rev Cell Mol Biol"},{"key":"pone.0263369.ref031","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1749-6632.2009.05030.x","article-title":"Pathophysiological consequences of HIF activation: HIF as a modulator of fibrosis","volume":"1177","author":"VH Haase","year":"2009","journal-title":"Ann N Y Acad Sci"},{"key":"pone.0263369.ref032","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1161\/01.RES.0000134644.89917.96","article-title":"Uncontrolled expression of vascular endothelial growth factor and its receptors leads to insufficient skin angiogenesis in patients with systemic sclerosis","volume":"95","author":"Distler Oliver","year":"2004","journal-title":"Circ. 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