Fibroblast growth factor receptor-1 (FGFR1) in vascular smooth muscle cell phenotypic switch

Vascular smooth muscle cells (VSMCs) play a critical role in the physiological maintenance of the cardiovascular system. In contrast to skeletal and cardiac muscle cells, VSMCs have the capacity to modulate their phenotype from contractile to synthetic and proliferative states. This phenotypic switch plays an important role in pathological processes, including hypertension, atherosclerosis, and restenosis alter angioplasty. Understanding the molecular mechanism of how VSMCs modulate their phenotype is an important step in the understanding of cardiovascular disease.;My studies have focused on examining the mechanism of VSMC phenotypic modulation by fibroblast growth factor receptor-1 (FGFR1). I have developed a set of FGFR1 pathway-deficient mutants to examine the signaling pathway(s) mediated by FGFR1 that control VSMC phenotype. My results showed that the FGFR1-mediated FRS2 pathway, but not the Crk or PLCgamma pathways, is required for regulating VSMC phenotype. This is the first reported evidence that FRS2 participates in VSMC phenotypic modulation.;In addition to FGF, platelet-derived growth factor (PDGF) is a well documented growth factor that regulates switching of VSMC from a contractile phenotype to proliferative and synthetic phenotype. I found that FGF2 and PDGF-BB modulate VSMC phenotype including increase cell proliferation and decrease smooth muscle marker gene expression. I also found that FGFR1 co-immunoprecipitated with PDGFRbeta. This complex formation does not require receptor activation and is mediated through both the extracellular and intracellular domains. Moreover, FRS2 knockdown in VSMC reversed FGF2 and PDGF-BB mediated downregulation of smooth muscle marker gene expression; while leaving PDGF-BB-induced ERK activation and cell proliferation intact.;FRS2 is an adaptor protein linking FGFR to downstream MAP kinase and Akt/mTOR signaling. My biochemical studies showed that mTOR is a downstream target of FGFR1/FRS2. FGFR1 activation phosphorylated mTOR at Ser2448 site and mTOR inhibitor rapamycin partially reversed FGFR1-mediated VSMC phenotypic switch by increasing SM alpha-actin protein synthesis. In addition, mTOR was co-immunoprecipitated with activated FGFR1/FRS2.;In summary, the results of this study will provide information on FGFR1 signaling in VSMC phenotypic switch and also set the stage for future design of new drugs that may selectively block FGFR1 signaling for pharmacological interventions.