An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression
An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression
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DOI：
10.1074/jbc.m105474200
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发表时间：
2001-09-07
影响因子：
4.8
通讯作者：
Clauss, M
中科院分区：
文献类型：
--
作者：
Blum, S;Issbrüker, K;Clauss, M
血管内皮生长因子(VEGF)不仅对血管生成和血管生成是必不可少的，而且还能诱导内皮细胞中凝血的主要起始者组织因子。在这项研究中，我们分析了血管内皮生长因子诱导人脐静脉内皮细胞产生组织因子的途径。使用特定的低分子量抑制剂，我们可以证明p38和ER-k-1/2丝裂原激活蛋白(ALA-P)激酶的关键作用。相反，用磷脂酰肌醇3(P13)-激酶的抑制剂Wortmannin或LY294002处理后，可显著增强血管内皮细胞生长因子诱导的组织因子的产生，表明P13-激酶对组织因子诱导通路具有负调控作用。因此，带有结构性活性Akt的转导导致了血管内皮生长因子诱导的组织因子产生的减少。用磷酸化p38的特异性抗体进行的Western印迹分析表明，与单独使用任何一种试剂相比，在Wortmannin存在的情况下，用VEGF刺激人脐静脉内皮细胞时，这种MAPK的激活程度更高。因此，P13-激酶通路对血管内皮细胞组织因子活性的负性调节至少部分可以通过抑制这一MAPK信号通路来解释。这是首次证明促凝血剂活性与P13-激酶-Akt信号通路之间的相互关系，并揭示了一种新的机制，即组织因子在内皮细胞中的表达可以被控制。
Vascular endothelial growth factor (VEGF) is not only essential for vasculogenesis and angiogenesis but is also capable of inducing tissue factor, the prime initiator of coagulation, in endothelial cells. In this study we have analyzed the VEGF-elicited pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells. Using specific low molecular weight inhibitors we could demonstrate a crucial role of the p38 and Er-k-1/2 mitogen-activated protein (ALA-P) kinases. In contrast, treatment with wortmannin or LY294002, inhibitors of phosphatidylinositol 3 (P13)-kinase, resulted in a strong enhancement of the VEGF-induced tissue factor production, indicating a negative regulatory role of the P13-kinase on tissue factor-inducing pathways. Accordingly, transduction with constitutively active Akt led to a reduction of VEGF-induced tissue factor production. Western blot analyses using antibodies specific, for phosphorylated p38 showed an enhanced activation of this MAP kinase in human umbilical cord vein endotheIial cells when stimulated with VEGF in the presence of wortmannin in comparison to either agent alone. Thus, the negative regulation of the P13-kinase pathway on endotheIial tissue factor activity can be explained at least in part by a suppression of this Map kinase-signaling pathway. This is the first demonstration of a reciprocal relationship between procoagulant activity and the P13-kinase-Akt signaIing pathway, and it reveals a novel mechanism by which tissue factor expression can be controlled in endothelial cells.