Angiopoietin-1 regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway

Angiopoietin-1 (Ang1) is a strong apoptosis survival factor for endothelial cells, In this study, the receptor/second messenger signal transduction pa thway for the antiapoptotic effect of Ang1 on human umbilical vein endothel ial cells was examined. Pretreatment with soluble Tie2 receptor, but not Ti e1 receptor, blocked the Ang1-induced antiapoptotic effect. Ang1 induced ph osphorylation of Tie2 and the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase) and increased PI 3'-kinase activity in a dose-dependent man ner. The PI 3'-kinase-specific inhibitors wortmannin and LY294002 blocked t he Ang1-induced antiapoptotic effect. Ang1 induced phosphorylation of the s erine-threonine kinase Akt at Ser473 in a PI 3'-kinase- dependent manner. E xpression of a dominant-negative form of Akt reversed the Ang1-induced anti apoptotic effect. Ang1 mRNA and protein were present in vascular smooth mus cle cells but not in endothelial cells. Cultured vascular smooth muscle cel ls, but not human umbilical vein endothelial cells, secreted Ang1, These fi ndings indicate that the Tie2 receptor, PI3'-kinase, and Akt are crucial el ements in the signal transduction pathway leading to endothelial cell survi val induced by the paracrine activity of Ang1.