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When overexpressed, cysteine\u2010rich angiogenic inducer 61 (CYR<\/jats:styled-content>\u201061) promoted angiogenesis in SS<\/jats:styled-content>c EC<\/jats:styled-content>s. This study was undertaken to examine the role of CYR<\/jats:styled-content>\u201061 in fibrosis and determine the mechanisms involved in CYR<\/jats:styled-content>\u201061\u2013mediated angiogenesis in SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>Methods<\/jats:title>Dermal EC<\/jats:styled-content>s and fibroblasts were isolated from biopsy specimens from healthy subjects and patients with SS<\/jats:styled-content>c. CYR<\/jats:styled-content>\u201061 level was determined by quantitative polymerase chain reaction, Western blotting, and enzyme\u2010linked immunosorbent assay. CYR<\/jats:styled-content>\u201061 was overexpressed using a CYR<\/jats:styled-content>61<\/jats:italic> vector or knocked down using small interfering RNA<\/jats:styled-content>, and functional and mechanistic studies were then conducted in fibroblasts and EC<\/jats:styled-content>s.<\/jats:p><\/jats:sec>Results<\/jats:title>Lower CYR<\/jats:styled-content>61<\/jats:italic> messenger RNA<\/jats:styled-content> levels were observed in dermal fibroblasts and EC<\/jats:styled-content>s from SS<\/jats:styled-content>c patients than in those from healthy controls. In SS<\/jats:styled-content>c fibroblasts, overexpression of CYR<\/jats:styled-content>\u201061 led to significant reduction in the expression of profibrotic genes, including COL<\/jats:styled-content>1A1<\/jats:italic> (P<\/jats:italic> = 0.002) and ACTA<\/jats:styled-content>2<\/jats:italic> (P<\/jats:italic> = 0.04), and an increase in the expression of matrix\u2010degrading genes, including MMP<\/jats:styled-content>1<\/jats:italic> (P<\/jats:italic> = 0.002) and MMP<\/jats:styled-content>3<\/jats:italic> (P<\/jats:italic> =0.004), and proangiogenic VEGF<\/jats:styled-content><\/jats:italic> (P<\/jats:italic> = 0.03). The antifibrotic effect of CYR<\/jats:styled-content>\u201061 was further demonstrated by delay in wound healing, inhibition of gel contraction, inactivation of the transforming growth factor \u03b2 pathway, and early superoxide production associated with senescence in SS<\/jats:styled-content>c fibroblasts. In SS<\/jats:styled-content>c EC<\/jats:styled-content>s, overexpression of CYR<\/jats:styled-content>\u201061 led to increased production of vascular endothelial cell growth factor. The proangiogenic effects of CYR<\/jats:styled-content>\u201061 were mediated by signaling through \u03b1v\u03b23 receptors and downstream activation of AMP<\/jats:styled-content>\u2010activated protein kinase, AKT<\/jats:styled-content>, and the endothelial cell nitric oxide synthase\/nitric oxide pathway system.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>CYR<\/jats:styled-content>\u201061, which is epigenetically regulated by HDAC<\/jats:styled-content>\u20105, is a potent antifibrotic and proangiogenic mediator in SS<\/jats:styled-content>c. Therapeutic intervention to promote CYR<\/jats:styled-content>\u201061 activity or increase CYR<\/jats:styled-content>\u201061 levels might be of benefit in SS<\/jats:styled-content>c.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40890","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T23:16:28Z","timestamp":1552950988000},"page":"1350-1359","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Identification of Cysteine\u2010Rich Angiogenic Inducer 61 as a Potential Antifibrotic and Proangiogenic Mediator in Scleroderma"],"prefix":"10.1002","volume":"71","author":[{"given":"Pei\u2010Suen","family":"Tsou","sequence":"first","affiliation":[{"name":"University of Michigan Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Khanna","sequence":"additional","affiliation":[{"name":"University of Michigan Ann 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