Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia-Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide-Dependent Mechanisms.
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Promotes Angiogenesis and Ischemia-Induced Neovascularization Via NADPH Oxidase 4 (NOX4) and Nitric Oxide-Dependent Mechanisms.
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DOI：
10.1161/jaha.115.002527
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发表时间：
2015-11-16
影响因子：
5.4
通讯作者：
Kavurma MM
中科院分区：
文献类型：
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作者：
Di Bartolo BA;Cartland SP;Prado-Lourenco L;Griffith TS;Gentile C;Ravindran J;Azahri NS;Thai T;Yeung AW;Thomas SR;Kavurma MM
肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有通过诱导内皮细胞死亡来抑制血管生成的能力，并且能够在体外促进促血管生成活性。这些看似相反的作用使其在缺血性疾病中的作用尚不清楚。使用Trail - / -和野生型小鼠，我们试图确定Trail在后肢缺血后血管生成和新生血管中的作用。通过实时三维Vevo超声成像和CD31染色评估，Trail - / -小鼠缺血后血管化明显减少，并与毛细血管形成减少和细胞凋亡增加有关。值得注意的是，腺病毒TRAIL处理显著改善了TRAIL - / -和野生型小鼠的肢体灌注、毛细血管密度和血管平滑肌细胞含量。成纤维细胞生长因子- 2是一种有效的血管生成因子，可增加TRAIL在人微血管内皮细胞- 1中的表达，TRAIL siRNA可抑制成纤维细胞生长因子- 2介导的增殖、迁移和小管形成。成纤维细胞生长因子- 2和TRAIL均显著增加NADPH氧化酶4 （NOX4）的表达。靶向NOX4的sirna抑制了TRAIL‐诱导的体外血管生成活性，与此一致的是，在TRAIL−/−小鼠缺血3天的后肢中，NOX4 mRNA减少。此外，通过清除H2O2或抑制一氧化氮合酶活性，TRAIL诱导的增殖、迁移和小管形成被阻断。重要的是，TRAIL诱导的内皮一氧化氮合酶Ser - 1177位点磷酸化和细胞内人微血管内皮细胞- 1细胞一氧化氮水平依赖于NOX4。这是第一个在体内证明TRAIL可以促进后肢缺血后血管生成的报道。TRAIL对人微血管内皮细胞- 1的血管生成作用位于成纤维细胞生长因子- 2的下游，涉及NOX4和一氧化氮信号。这些数据具有重要的治疗意义，例如TRAIL可以改善心血管疾病和糖尿病患者对缺血的血管生成反应，并增加灌注恢复。
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. Reduced vascularization assessed by real‐time 3‐dimensional Vevo ultrasound imaging and CD31 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 siRNA. Both fibroblast growth factor‐2 and TRAIL significantly increased NADPH oxidase 4 (NOX4) expression. TRAIL‐inducible angiogenic activity in vitro was inhibited with siRNAs targeting NOX4, and consistent with this, NOX4 mRNA was reduced in 3‐day ischemic hindlimbs of Trail −/− mice. Furthermore, TRAIL‐induced proliferation, migration, and tubule formation was blocked by scavenging H2O2, 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 NOX4 dependent. 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 NOX4 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.