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We sought to identify mRNA and microRNA transcripts that were differentially regulated following HLI, based on the ischemic muscle having intact, or reduced, IL-21\/IL21R signaling. In this comparison, 200 mRNAs were differentially expressed but only six microRNA (miR)\/miR clusters (and among these only miR-30b) were upregulated in EC isolated from ischemic muscle. Next, myoglobin-overexpressing transgenic (MgTG) C57BL\/6 mice examined following HLI and IL-21 overexpression displayed greater angiogenesis, better perfusion recovery, and less tissue necrosis, with increased miR-30b expression. In EC cultured under hypoxia serum starvation, knock-down of miR-30b reduced, while overexpression of miR-30b increased IL-21-mediated EC survival and angiogenesis. In Il21r\u2212\/\u2212 mice following HLI, miR-30b overexpression vs. control improved perfusion recovery, with a reduction of suppressor of cytokine signaling 3, a miR-30b target and negative regulator of STAT3. Together, miR-30b appears both necessary and sufficient for IL21\/IL-21R-mediated angiogenesis and may present a new therapeutic option to treat PAD if the IL21R is not available for activation.<\/jats:p>","DOI":"10.3390\/ijms23010271","type":"journal-article","created":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T01:18:15Z","timestamp":1640654295000},"page":"271","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["MicroRNA-30b Is Both Necessary and Sufficient for Interleukin-21 Receptor-Mediated Angiogenesis in Experimental Peripheral Arterial Disease"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-1648","authenticated-orcid":false,"given":"Tao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou 510120, China"},{"name":"Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-6977","authenticated-orcid":false,"given":"Liang","family":"Yang","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Department of Pharmacology, Nankai University, Tianjing 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjie","family":"Yuan","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430070, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Farber","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanne","family":"Spolski","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and the Immunology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Warren J.","family":"Leonard","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology and the Immunology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2967-8320","authenticated-orcid":false,"given":"Vijay C.","family":"Ganta","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Vascular Biology Center and Department of Medicine, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-8243","authenticated-orcid":false,"given":"Brian H.","family":"Annex","sequence":"additional","affiliation":[{"name":"Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA"},{"name":"Vascular Biology Center and Department of Medicine, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nrcardio.2013.70","article-title":"Therapeutic angiogenesis for critical limb ischaemia","volume":"10","author":"Annex","year":"2013","journal-title":"Nat. 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