Antisense Inhibition of Basic Fibroblast Growth Factor Induces Apoptosis in Vascular Smooth Muscle Cells

Basic fibroblast growth factor (bFGF), a potent mitogen for many cell types, is expressed by vascular smooth muscle cells and plays a prominent role in the proliferative response to vascular injury. Basic FGF has also been implicated as a survival factor for a variety of quiescent or terminally differentiated cells. Autocrine mechanisms could potentially mediate both proliferation and cell survival. To probe such autocrine pathways, endogenous bFGF production was inhibited in cultured rat vascular smooth muscle cells by the expression of antisense bFGF RNA. Inhibition of endogenous bFGF production induced apoptosis in these cells independent of proliferation, and apoptosis could be prevented by exogenous bFGF but not serum or epidermal growth factor. The induction of apoptosis was associated with an inappropriate entry into S phase. These data demonstrate that interruption of autocrine bFGF signaling results in apoptosis of vascular smooth muscle cells, and that the mechanism involves disruption of normal cell cycle regulation.