| Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells without harming normal cells supporting its potential as a cancer therapy. However, the normal physiological roles of TRAIL on the human vascular endothelium are not well studied. Endothelial apoptosis plays important roles in both physiological and pathological processes including atherosclerosis and angiogenesis. The phosphatidylinositol-3 kinase (PI3K)/Akt pathway is of central importance to the vascular endothelium during angiogenesis, where it regulates endothelial cell survival, differentiation and migration. We demonstrate in this study that endothelial cells are resistant to TRAIL-induced apoptosis, but that inhibition of the PI3K pathway sensitizes them to TRAIL-induced apoptosis, through both the extrinsic and intrinsic pathways, by removing molecular inhibition of c-FLIP at the TRAIL death-inducing signaling complex (DISC). Hence, the PI3K/Akt pathway acting through c-FLIP could potentially determine endothelial susceptibility to TRAIL-induced apoptosis during vascular remodelling. |
