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.