Restoration of E2F expression rescues vascular endothelial cells from tumor necrosis factor-alpha-induced apoptosis

Background-Normally, quiescent endothelial cells (EC) line the inner surfac e of arteries and protect against thrombosis and neointimal growth. A varie ty of noxious stimuli, including balloon angioplasty, may compromise EC int egrity, thereby initiating proliferation and triggering the local release o f cytokines, including tumor necrosis factor-alpha (TNF-alpha). Methods and Results-In vivo blockade of TNF-alpha using a soluble receptor molecule results in accelerated reendothelialization at sites of balloon an gioplasty, suggesting an important physiological role of TNF-alpha in atten uating regrowth of endothelium after balloon angioplasty. Our studies revea l that TNF-alpha, an apoptosis-inducing cytokine, induces G1 cell-cycle arr est in proliferating EC, Quiescent EC are relatively immune to TNF-induced apoptosis versus proliferating EC, which display repression of the E2F tran scription factor coincident with TNF-induced apoptosis and cell-cycle arres t. We also show that in this setting, E2F overexpression exerts a survival effect in proliferating EC and restores cell-cycle progression, in direct c ontrast to results of prior reports, which revealed that deregulated expres sion of E2F in normally cycling cells induces apoptosis. Conclusions-These data demonstrate that TNF-induced apoptosis is highly dep endent on cell-cycle activity and that E2F can function as survival factor under certain conditions.