An inhibitory role of the phosphatidylinositol 3-kinase-signaling pathway in vascular endothelial growth factor-induced tissue factor expression

Vascular endothelial growth factor (VEGF) is not only essential for vasculo genesis and angiogenesis but is also capable of inducing tissue factor, the prime initiator of coagulation, in endothelial cells. In this study we hav e analyzed the VEGF-elicited pathways involved in the induction of tissue f actor in human umbilical cord vein endothelial cells. Using specific low mo lecular weight inhibitors we could demonstrate a crucial role of the p38 an d Er-k-1/2 mitogen-activated protein (ALA-P) kinases. In contrast, treatmen t with wortmannin or LY294002, inhibitors of phosphatidylinositol 3 (P13)-k inase, resulted in a strong enhancement of the VEGF-induced tissue factor p roduction, indicating a negative regulatory role of the P13-kinase on tissu e factor-inducing pathways. Accordingly, transduction with constitutively a ctive Akt led to a reduction of VEGF-induced tissue factor production. West ern blot analyses using antibodies specific, for phosphorylated p38 showed an enhanced activation of this MAP kinase in human umbilical cord vein endo theIial cells when stimulated with VEGF in the presence of wortmannin in co mparison to either agent alone. Thus, the negative regulation of the P13-ki nase pathway on endotheIial tissue factor activity can be explained at leas t in part by a suppression of this Map kinase-signaling pathway. This is th e first demonstration of a reciprocal relationship between procoagulant act ivity and the P13-kinase-Akt signaIing pathway, and it reveals a novel mech anism by which tissue factor expression can be controlled in endothelial ce lls.