Regulation of endothelial cell apoptosis by Vascular Endothelial Growth Inhibitor (VEGI) and death receptor 3 (DR3).

摘要

Vascular Endothelial Growth Inhibitor (VEGI) is an endothelial cell autocrine factor and a member of the tumor necrosis family of ligands. VEGI is able to specifically inhibit endothelial cell growth and is an efficient inhibitor of angiogenesis. The molecular mechanisms of VEGI activity on endothelial cells remain undefined. Here we focused on two important steps in the signal transduction of VEGI. We first determined a role of NF-kappaB in VEGI-induced apoptosis. We found that inhibition of the NF-kappaB pathway resulted in an increased apoptotic potential of VEGI. We conclude that the NF-kappaB pathway plays a role in suppressing the apoptotic potential of VEGI. We next investigated the receptor responsible for VEGI-induced endothelial cell apoptosis. DR3 is a receptor for VEGI and thus we first focused on confirming if DR3 is the receptor responsible for VEGI-mediated endothelial cell death. We determined VEGI had diminished apoptotic activity in endothelial cells that are depleted of DR3 by siRNA. However, it was determined that the apoptotic stimuli, LPS and TNFalpha, were also unable to mediate cell death in DR3-depleted endothelial cells. We conclude that DR3 is mediating an intracellular event that is involved in controlling the apoptotic pathway. This is a novel role of DR3 that is yet to be described. However, this role of DR3 interferes with our analysis of the ligand/receptor relationship and therefore we were unable to confirm that DR3 is the receptor responsible for VEGI-induced apoptosis. We also provide preliminary evidence that VEGI is utilizing an unknown receptor to mediate NF-kappaB activation. We therefore provide several mechanisms to control VEGI-mediated endothelial cell death, one being the activation of NF-kappaB to suppress the apoptotic potential of VEGI and the needed presence of DR3 for VEGI to initiate apoptosis, a role that is possibly independent of ligand binding.