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Background  Tumor necrosis factor–related apoptosis‐inducing ligand ( TRAIL ) has the ability to inhibit angiogenesis by inducing endothelial cell death, as well as being able to promote pro‐angiogenic activity in vitro. These seemingly opposite effects make its role in ischemic disease unclear. Using  Trail   −/−   and wildtype mice, we sought to determine the role of  TRAIL  in angiogenesis and neovascularization following hindlimb ischemia.    Methods and Results  Reduced vascularization assessed by real‐time 3‐dimensional Vevo ultrasound imaging and  CD 31 staining was evident in  Trail   −/−   mice after ischemia, and associated with reduced capillary formation and increased apoptosis. Notably, adenoviral  TRAIL  administration significantly improved limb perfusion, capillary density, and vascular smooth‐muscle cell content in both  Trail   −/−   and wildtype mice. Fibroblast growth factor‐2, a potent angiogenic factor, increased  TRAIL  expression in human microvascular endothelial cell‐1, with fibroblast growth factor‐2‐mediated proliferation, migration, and tubule formation inhibited with  TRAIL  si RNA . Both fibroblast growth factor‐2 and  TRAIL  significantly increased NADPH oxidase 4 ( NOX 4) expression.  TRAIL ‐inducible angiogenic activity in vitro was inhibited with si RNA s targeting  NOX 4, and consistent with this,  NOX 4  mRNA  was reduced in 3‐day ischemic hindlimbs of  Trail   −/−   mice. Furthermore,  TRAIL ‐induced proliferation, migration, and tubule formation was blocked by scavenging H 2 O 2 , or by inhibiting nitric oxide synthase activity. Importantly,  TRAIL ‐inducible endothelial nitric oxide synthase phosphorylation at Ser‐1177 and intracellular human microvascular endothelial cell‐1 cell nitric oxide levels were  NOX 4 dependent.    Conclusions  This is the first report demonstrating that  TRAIL  can promote angiogenesis following hindlimb ischemia in vivo. The angiogenic effect of  TRAIL  on human microvascular endothelial cell‐1 cells is downstream of fibroblast growth factor‐2, involving  NOX 4 and nitric oxide signaling. These data have significant therapeutic implications, such that  TRAIL  may improve the angiogenic response to ischemia and increase perfusion recovery in patients with cardiovascular disease and diabetes.

journal of the american heart association

Tumor Necrosis Factor–Related Apoptosis‐Inducing Ligand ( TRAIL ) Promotes Angiogenesis and Ischemia‐Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide–Dependent Mechanisms