Regulation of angiogenesis by tissue factor cytoplasmic domain signaling
Regulation of angiogenesis by tissue factor cytoplasmic domain signaling
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DOI：
10.1038/nm1037
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发表时间：
2004-05-01
期刊：
影响因子：
82.9
通讯作者：
Ruf, W
中科院分区：
文献类型：
--
作者：
Belting, M;Dorrell, MI;Ruf, W
止血启动血管生成依赖伤口愈合，血栓形成经常与晚期癌症有关。虽然凝血激活可以产生有效的血管生成调节因子，但对于这一途径如何在体内支持血管生成知之甚少。本研究表明，组织因子(TF)-VIIa蛋白酶复合物，不需要触发凝血，可以通过蛋白酶激活受体-2 （PAR-2）信号传导促进肿瘤和发育性血管生成。在这种情况下，TF细胞质结构域负调控PAR-2信号。TF细胞质结构域缺失的小鼠（TFDeltaCT小鼠）表现出与血小板衍生生长因子BB （PDGF-BB）协同作用的par -2依赖性血管生成增强。糖尿病患者眼组织显示PAR-2与磷酸化的TF共定位，特异性地作用于新生血管，表明TF胞质结构域的磷酸化释放了其对血管生成中PAR-2信号的负调控。因此，靶向TF-VIIa信号通路可能会提高血管抑制剂治疗癌症和新生血管性眼病的疗效。
Hemostasis initiates angiogenesis-dependent wound healing, and thrombosis is frequently associated with advanced cancer. Although activation of coagulation generates potent regulators of angiogenesis, little is known about how this pathway supports angiogenesis in vivo. Here we show that the tissue factor (TF)-VIIa protease complex, independent of triggering coagulation, can promote tumor and developmental angiogenesis through protease-activated receptor-2 (PAR-2) signaling. In this context, the TF cytoplasmic domain negatively regulates PAR-2 signaling. Mice from which the TF cytoplasmic domain has been deleted (TFDeltaCT mice) show enhanced PAR-2-dependent angiogenesis, in synergy with platelet-derived growth factor BB (PDGF-BB). Ocular tissue from diabetic patients shows PAR-2 colocalization with phosphorylated TF specifically on neovasculature, suggesting that phosphorylation of the TF cytoplasmic domain releases its negative regulatory control of PAR-2 signaling in angiogenesis. Targeting the TF-VIIa signaling pathway may thus enhance the efficacy of angiostatic treatments for cancer and neovascular eye diseases.