Angiopoietin-2 at high concentration can enhance endothelial cell survivalthrough the phosphatidylinositol 3 '-kinase/Akt signal transduction pathway

The angiopoietin-Tie2 system in endothelial cells is an important regulator of vasculogenesis and vascular integrity, High levels of angiopoietin-2 (A ng2) mRNA are observed in vascular activation during tumorigenesis. Althoug h Ang2 is known to be a naturally occurring antagonist of angiopoietin-1 (A ng1) in vivo, the exact function of Ang2 itself is not known. Here, we foun d that a high concentration of Ang2 (800 ng/ml) acts as an apoptosis surviv al factor for endothelial cells during serum deprivation apoptosis, The sur vival effect of high concentration Ang2 was blocked by pre-treatment with s oluble Tie2 receptor and the PI 3'-kinase-specific inhibitors, wortmannin a nd LY294002. Accordingly, 800 ng/ml of Ang2 induced phosphorylation of Tie2 , the p85 subunit of phosphatidylinositol 3'-kinase (PI 3'-kinase), and ser ine-threonine kinase Akt at Ser473 in the human umbilical vein endothelial cells; lower concentrations of Ang2 (50-400 ng/ml) did not produce notable effects. These findings indicate that at high concentrations, Ang2, like An g1, can be an apoptosis survival factor for endothelial cells through the a ctivation of the Tie2 receptor, PI 3'-kinase and Akt, and thus may be a pos itive regulator of tumor angiogenesis.