Angiopoietin-1 inhibits irradiation- and mannitol-induced apoptosis in endothelial cells

Background and Purpose - Angiopoietin-1 (Ang1) is a vasculogenic factor that signals through the endothelial cell-specific Tie2 receptor tyrosine kinase. We recently reported that Ang1 prevented apoptosis induced by serum deprivation in endothelial cells. In this study, we examined whether Ang1 prevents apoptosis in endothelial cells treated with irradiation or clinical concentrations of mannitol. Methods and Results - Ang1 prevented irradiation- and mannitol-induced apoptosis in human umbilical vein endothelial cells in a dose-dependent manner. Pretreatment with soluble Tie2 receptor, but not Tie1 receptor, blocked the antiapoptotic effect of Ang1. Two phosphatidylinositol 3'-kinase (PI3-kinase)-specific inhibitors, wortmannin and LY294002, blocked the Ang1-induced antiapoptotic effect. The antiapoptotic potency of Ang1 was similar to or greater than that of vascular endothelial growth factor, basic fibroblast growth factor, and endothelin-1. Ang1 also prevented apoptosis in cultured endothelial cells from porcine pulmonary and coronary arteries and in endothelial cells of explanted rat aorta. Conclusions - Ang1 promotes the survival of endothelial cells in irradiation- and mannitol-induced apoptosis through Tie2 receptor binding and PI3-kinase activation. Pretreatment with Ang1 could be beneficial in maintaining normal endothelial cell integrity during intracoronary irradiation or systemic mannitol therapy.