{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:46:25Z","timestamp":1790790385878,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T00:00:00Z","timestamp":1480291200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Vascular dysfunction represents a disease\u2010initiating event in systemic sclerosis (SSc; scleroderma). Results of recent studies suggest that epigenetic dysregulation impairs normal angiogenesis and can result in abnormal patterns of blood vessel growth. Histone deacetylases (HDACs) control endothelial cell (EC) proliferation and regulate EC migration. Specifically, HDAC\u20105 appears to be antiangiogenic. This study was undertaken to test whether HDAC\u20105 contributes to impaired angiogenesis in SSc by repressing proangiogenic factors in ECs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Dermal ECs were isolated from patients with diffuse cutaneous SSc and healthy controls. Angiogenesis was assessed using an in vitro Matrigel tube formation assay. An assay for transposase\u2010accessible chromatin using sequencing (ATAC\u2010seq) was performed to assess and localize the genome\u2010wide effects of <jats:italic>HDAC5<\/jats:italic> knockdown on chromatin accessibility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression of <jats:italic>HDAC5<\/jats:italic> was significantly increased in ECs from patients with SSc compared to healthy control ECs. Silencing of <jats:italic>HDAC5<\/jats:italic> in SSc ECs restored normal angiogenesis. <jats:italic>HDAC5<\/jats:italic> knockdown followed by ATAC\u2010seq assay in SSc ECs identified key <jats:italic>HDAC5<\/jats:italic>\u2010regulated genes involved in angiogenesis and fibrosis, such as <jats:italic>CYR61<\/jats:italic>, <jats:italic>PVRL2<\/jats:italic>, and <jats:italic>FSTL1<\/jats:italic>. Simultaneous knockdown of <jats:italic>HDAC5<\/jats:italic> in conjunction with either <jats:italic>CYR61<\/jats:italic>, <jats:italic>PVRL2<\/jats:italic>, or <jats:italic>FSTL1<\/jats:italic> inhibited angiogenesis in SSc ECs. Conversely, overexpression of these genes individually led to an increase in tube formation as assessed by Matrigel assay, suggesting that these genes play functional roles in the impairment of angiogenesis in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Several novel <jats:italic>HDAC5<\/jats:italic>\u2010regulated target genes associated with impaired angiogenesis were identified in SSc ECs by ATAC\u2010seq. The results of this study provide a potential link between epigenetic regulation and impaired angiogenesis in SSc, and identify a novel mechanism for the dysregulated angiogenesis that characterizes this disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39828","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T10:42:51Z","timestamp":1470220971000},"page":"2975-2985","source":"Crossref","is-referenced-by-count":70,"title":["Histone Deacetylase 5 Is Overexpressed in Scleroderma Endothelial Cells and Impairs Angiogenesis via Repression of Proangiogenic Factors"],"prefix":"10.1002","volume":"68","author":[{"given":"Pei\u2010Suen","family":"Tsou","sequence":"first","affiliation":[{"name":"University of Michigan Ann Arbor"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D.","family":"Wren","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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