Autocrine signaling through Ras prevents apoptosis in vascular smooth muscle cells in vitro

Vascular smooth muscle cell (SMC) apoptosis contributes to physiological an d pathological vascular remodeling, Autocrine fibroblast growth factor (FGF ) signaling promotes survival in SMC in vitro. Interruption of autocrine FG F signaling results in apoptosis that can be rescued by other growth factor s such as PDGF (platelet-derived growth factor) or EGF (epidermal, growth f actor). Such heterologous growth factor rescue is prevented by pharmacologi cal inhibition of MAPK, implicating signaling through Ras in mediating surv ival. This study was designed to test the hypothesis that signaling through Ras is both necessary and sufficient to mediate SMC survival in vitro. Rec ombinant adenoviruses encoding dominant-negative (Ras(N17)) and constitutiv ely active (Ras(L61)) mutants of Ras were used. Ras(N17) blocks growth fact or-mediated MAPK activation and can itself induce SMC apoptosis. Ras(N17) i s synergistic with inhibition of autocrine FGF signaling in triggering apop tosis and prevents heterologous growth factor rescue. Conversely, Ras(L61) prevents apoptosis resulting from inhibition of autocrine FGF signaling. Re scue by Ras(L61) can be partially prevented by pharmacological inhibition o f MEK or phosphatidylinositol 3-kinase, two downstream effecters of Ras. Th ese results suggest that Ras signaling is both necessary and sufficient to mediate survival in SMC in vitro. Further work is required to determine how these signaling events are regulated in the context of vascular remodeling in vivo.