
<ArticleTitle>An inhibitory role of the <prot>phosphatidylinositol 3-kinase</prot>-signaling pathway in <prot>vascular endothelial growth factor</prot>-induced tissue factor expression.</ArticleTitle>
<AbstractText><prot>Vascular endothelial growth factor</prot> (<prot>VEGF</prot>) 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 <prot>VEGF</prot>-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 <prot>p38</prot> and <prot>Erk-1</prot>/2 mitogen-activated protein (MAP) kinases. In contrast, treatment with wortmannin or LY294002, inhibitors of <prot>phosphatidylinositol 3 (PI3)-kinase</prot>, resulted in a strong enhancement of the <prot>VEGF</prot>-induced tissue factor production, indicating a negative regulatory role of the <prot>PI3-kinase</prot> on tissue factor-inducing pathways. Accordingly, transduction with constitutively active <prot>Akt</prot> led to a reduction of <prot>VEGF</prot>-induced tissue factor production. Western blot analyses using antibodies specific for phosphorylated <prot>p38</prot> showed an enhanced activation of this MAP kinase in human umbilical cord vein endothelial cells when stimulated with <prot>VEGF</prot> in the presence of wortmannin in comparison to either agent alone. Thus, the negative regulation of the <prot>PI3-kinase</prot> pathway on <prot>endothelial tissue factor</prot> 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 <prot>PI3-kinase</prot>-<prot>Akt</prot> signaling pathway, and it reveals a novel mechanism by which tissue factor expression can be controlled in endothelial cells.</AbstractText>
