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Using<jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>and wildtype mice, we sought to determine the role of<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>in angiogenesis and neovascularization following hindlimb ischemia.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Methods and Results<\/jats:title><jats:p xml:lang=\"en\">Reduced vascularization assessed by real\u2010time 3\u2010dimensional Vevo ultrasound imaging and<jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>31 staining was evident in<jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>administration significantly improved limb perfusion, capillary density, and vascular smooth\u2010muscle cell content in both<jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>and wildtype mice. Fibroblast growth factor\u20102, a potent angiogenic factor, increased<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>expression in human microvascular endothelial cell\u20101, with fibroblast growth factor\u20102\u2010mediated proliferation, migration, and tubule formation inhibited with<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>. Both fibroblast growth factor\u20102 and<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>significantly increased NADPH oxidase 4 (<jats:styled-content style=\"fixed-case\">NOX<\/jats:styled-content>4) expression.<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>\u2010inducible angiogenic activity in\u00a0vitro was inhibited with si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>s targeting<jats:styled-content style=\"fixed-case\">NOX<\/jats:styled-content>4, and consistent with this,<jats:styled-content style=\"fixed-case\">NOX<\/jats:styled-content>4<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>was reduced in 3\u2010day ischemic hindlimbs of<jats:italic>Trail<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup>mice. Furthermore,<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>\u2010induced proliferation, migration, and tubule formation was blocked by scavenging H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>, or by inhibiting nitric oxide synthase activity. Importantly,<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>\u2010inducible endothelial nitric oxide synthase phosphorylation at Ser\u20101177 and intracellular human microvascular endothelial cell\u20101 cell nitric oxide levels were<jats:styled-content style=\"fixed-case\">NOX<\/jats:styled-content>4 dependent.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Conclusions<\/jats:title><jats:p xml:lang=\"en\">This is the first report demonstrating that<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>can promote angiogenesis following hindlimb ischemia in\u00a0vivo. The angiogenic effect of<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>on human microvascular endothelial cell\u20101 cells is downstream of fibroblast growth factor\u20102, involving<jats:styled-content style=\"fixed-case\">NOX<\/jats:styled-content>4 and nitric oxide signaling. These data have significant therapeutic implications, such that<jats:styled-content style=\"fixed-case\">TRAIL<\/jats:styled-content>may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes.<\/jats:p><\/jats:sec>","DOI":"10.1161\/jaha.115.002527","type":"journal-article","created":{"date-parts":[[2015,11,17]],"date-time":"2015-11-17T02:33:15Z","timestamp":1447727595000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Tumor Necrosis Factor\u2013Related Apoptosis\u2010Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia\u2010Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide\u2013Dependent Mechanisms"],"prefix":"10.1161","volume":"4","author":[{"given":"Belinda Ann","family":"Di Bartolo","sequence":"first","affiliation":[{"name":"The Heart Research Institute, Sydney, NSW, Australia"},{"name":"The University of 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