AUTOCRINE FGF SIGNALING IS REQUIRED FOR VASCULAR SMOOTH-MUSCLE CELL-SURVIVAL IN-VITRO

Expression of both basic fibroblast growth factor (bFGF) and FGF recep tors (FGFR) by vascular smooth muscle cells suggests that autocrine FG F signaling mechanisms may have important functions. inhibition of smo oth muscle cell bFGF expression provokes apoptosis, suggesting that en dogenous bFGF generates an anti-apoptotic signal. The purpose of this study was to determine whether the survival function of endogenous bFG F requires signaling through FGFR. A recombinant adenovirus encoding a truncated murine FGFR-1 lacking the kinase domain (DN-FGFR) efficient ly expressed the transgene in cultured rat aortic smooth muscle cells. The truncated receptor acted in a dominant negative fashion to effect ively prevent receptor-mediated signaling, assessed by phosphorylation of p42/p44 MAP kinase. Expression of DN-FGFR provoked apoptosis of SM C in a dose-dependent fashion that was insensitive to recombinant bFGF but could be rescued by platelet derived growth factor or epidermal g rowth factor. Heterologous growth factor rescue was inhibited by PD980 59, an inhibitor of MEK (MAP kinase-kinase). These data demonstrate th at inhibition of FGF receptor activation results in apoptosis and sugg est that an intact autocrine FGF signaling loop is required for vascul ar smooth muscle cell survival in vitro. These findings also implicate the Ras/Raf/MEK/MAP kinase cascade in generating or sustaining the su rvival signal. The functional significance of an autocrine FGF signali ng loop in non-transformed cells has important implications for cardio vascular development remodeling and disease. J. Cell. Physiol. 177:58- 67, 1998. (C) 1998 Wiley-Liss, Inc.