{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:11:05Z","timestamp":1788876665344,"version":"build-2803163510"},"reference-count":49,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T00:00:00Z","timestamp":1623888000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Impaired angiogenesis in scleroderma (SSc) is a critical component of SSc pathology. MicroRNA\u2010126 (miR\u2010126) is expressed in endothelial cells (MVECs) where it regulates VEGF responses by repressing the negative regulators of VEGF, including the sprouty\u2010related protein\u20101 (SPRED1), and phosphoinositide\u20103 kinase regulatory subunit 2 (PIK3R2). MVECs were isolated from SSc skin and matched subjects (n\u00a0=\u00a06). MiR\u2010126 expression was measured by qPCR and in situ hybridization. Matrigel\u2010based tube assembly was used to test angiogenesis. MiR\u2010126 expression was inhibited by hsa\u2010miR\u2010126 inhibitor and enhanced by hsa\u2010miR\u2010126 Mimic. Epigenetic regulation of miR\u2010126 expression was examined by the addition of epigenetic inhibitors (Aza and TSA) to MVECs and by bisulphite genomic sequencing of DNA methylation of the miR\u2010126 promoter region. MiR\u2010126 expression, as well as EGFL7 (miR\u2010126 host gene), in SSc\u2010MVECs and skin, was significantly down\u2010regulated in association with increased expression of SPRED1 and PIK3R2 and diminished response to VEGF. Inhibition of miR\u2010126 in NL\u2010MVECs resulted in reduced angiogenic capacity, whereas overexpression of miR\u2010126 in SSc\u2010MVECs resulted in enhanced tube assembly. Addition of Aza and TSA normalized miR\u2010126 and EGFL7 expression levels in SSc\u2010MVECs. Heavy methylation in miR\u2010126\/EGFL7 gene was noted. In conclusion, these results demonstrate that the down\u2010regulation of miR\u2010126 results in impaired VEGF responses.<\/jats:p>","DOI":"10.1111\/jcmm.16727","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T05:44:05Z","timestamp":1623908645000},"page":"7078-7088","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Epigenetic down\u2010regulation of microRNA\u2010126 in scleroderma endothelial cells is associated with impaired responses to VEGF and defective angiogenesis"],"prefix":"10.1111","volume":"25","author":[{"given":"Yongqing","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Immunology University of Toledo Medical Center Toledo OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Sun","sequence":"additional","affiliation":[{"name":"University of Chicago Pritzker School of Medicine Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4666-0250","authenticated-orcid":false,"given":"Bashar","family":"Kahaleh","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Immunology University of Toledo Medical Center Toledo OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/5345673"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2006.12.006"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601911423654"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2010.01027.x"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.323"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-6147(00)01676-X"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2005.tb00379.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.1.9"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1911"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar596"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000134644.89917.96"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.080516"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-004-0987-3"},{"key":"e_1_2_8_15_1","first-page":"641","article-title":"Increased but imbalanced expression of VEGF and its receptors has no positive effect on angiogenesis in systemic sclerosis skin","volume":"20","author":"Mackiewicz Z","year":"2002","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.07.008"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.07.002"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.40470"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4349"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.5301\/jsrd.5000217"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12105"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2013.00160"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.62"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.6"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1813006116"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.12.098"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.211706"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012156"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.25.15320"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.12.4056-4065.2003"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-5392-4"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.029736"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.108"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-015-2567-9"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707493105"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.02.002"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083294"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.05.007"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1086\/675980"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2247-0"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405189200"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01600-06"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/35088082"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.7240905"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.002576"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keu155"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0504-6"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121585"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-2076"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2012.05.011"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.16727","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jcmm.16727","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.16727","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:52:07Z","timestamp":1788875527000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.16727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,17]]},"references-count":49,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1111\/jcmm.16727"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.16727","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"value":"1582-1838","type":"print"},{"value":"1582-4934","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,17]]},"assertion":[{"value":"2020-11-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}