9731745

pubmed:Citation

1

Expression of both basic fibroblast growth factor (bFGF) and FGF receptors (FGFR) by vascular smooth muscle cells suggests that autocrine FGF signaling mechanisms may have important functions. Inhibition of smooth muscle cell bFGF expression provokes apoptosis, suggesting that endogenous bFGF generates an anti-apoptotic signal. The purpose of this study was to determine whether the survival function of endogenous bFGF requires signaling through FGFR. A recombinant adenovirus encoding a truncated murine FGFR-1 lacking the kinase domain (DN-FGFR) efficiently expressed the transgene in cultured rat aortic smooth muscle cells. The truncated receptor acted in a dominant negative fashion to effectively prevent receptor-mediated signaling, assessed by phosphorylation of p42/p44 MAP kinase. Expression of DN-FGFR provoked apoptosis of SMC in a dose-dependent fashion that was insensitive to recombinant bFGF but could be rescued by platelet derived growth factor or epidermal growth factor. Heterologous growth factor rescue was inhibited by PD98059, an inhibitor of MEK (MAP kinase-kinase). These data demonstrate that inhibition of FGF receptor activation results in apoptosis and suggest that an intact autocrine FGF signaling loop is required for vascular smooth muscle cell survival in vitro. These findings also implicate the Ras/Raf/MEK/MAP kinase cascade in generating or sustaining the survival signal. The functional significance of an autocrine FGF signaling loop in non-transformed cells has important implications for cardiovascular development, remodeling and disease.

eng

IM

MEDLINE

0021-9541

Print

NLM

58-67

pubmed-meshheading:9731745-Adenoviridae, pubmed-meshheading:9731745-Animals, pubmed-meshheading:9731745-Aorta, pubmed-meshheading:9731745-Apoptosis, pubmed-meshheading:9731745-Autocrine Communication, pubmed-meshheading:9731745-Calcium-Calmodulin-Dependent Protein Kinases, pubmed-meshheading:9731745-Cell Survival, pubmed-meshheading:9731745-Cells, Cultured, pubmed-meshheading:9731745-Enzyme Activation, pubmed-meshheading:9731745-Enzyme Inhibitors, pubmed-meshheading:9731745-Epidermal Growth Factor, pubmed-meshheading:9731745-Fibroblast Growth Factor 2, pubmed-meshheading:9731745-Flavonoids, pubmed-meshheading:9731745-Gene Expression Regulation, Viral, pubmed-meshheading:9731745-Mitogen-Activated Protein Kinase 1, pubmed-meshheading:9731745-Mitogen-Activated Protein Kinase 3, pubmed-meshheading:9731745-Mitogen-Activated Protein Kinases, pubmed-meshheading:9731745-Muscle, Smooth, Vascular, pubmed-meshheading:9731745-Prostaglandins F, pubmed-meshheading:9731745-Rats, pubmed-meshheading:9731745-Receptors, Fibroblast Growth Factor, pubmed-meshheading:9731745-Recombinant Fusion Proteins, pubmed-meshheading:9731745-ras Proteins

Autocrine FGF signaling is required for vascular smooth muscle cell survival in vitro.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't