Platelet-Derived Growth Factor-BB–Induced Human Smooth Muscle Cell Proliferation Depends on Basic FGF Release and FGFR-1 Activation

• Published in: Circulation research 2005-02, Vol.96 (2), p.172-179
• Main Authors: Millette, Esther, Rauch, Bernhard H, Defawe, Olivier, Kenagy, Richard D, Daum, Guenter, Clowes, Alexander W
• Format: Article
• Language: English
• Subjects: Aorta, Abdominal; Biological and medical sciences; Cell Division - drug effects; Cell Movement - drug effects; Cells, Cultured - drug effects; Cells, Cultured - metabolism; Chromones - pharmacology; DNA Replication - drug effects; Enzyme Activation - drug effects; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factor 2 - physiology; Fibroblast Growth Factor 2 - secretion; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Heparin - pharmacology; Humans; Indoles - pharmacology; Maleimides - pharmacology; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 2 - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Morpholines - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phosphorylation - drug effects; Platelet-Derived Growth Factor - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational - drug effects; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - physiology; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - physiology; Recombinant Proteins - pharmacology; RNA, Small Interfering - pharmacology; Tyrphostins - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000154595.87608.db

We have shown that the G protein–coupled receptor (GPCR) agonists, thrombin and Factor Xa, stimulate smooth muscle cell (SMC) proliferation through transactivation of the EGF receptor (EGFR) or the FGF receptor (FGFR), both of which are tyrosine kinase receptors. In the present study, we investigated whether platelet-derived growth factor (PDGF), a tyrosine kinase receptor agonist, might transactivate another tyrosine kinase receptor to induce SMC proliferation. Because heparin inhibits PDGF-mediated proliferation in human SMCs, we investigated whether the heparin-binding growth factor basic fibroblast growth factor (bFGF) and one of its receptors, FGFR-1, play a role in the response of human arterial SMCs to PDGF-BB. PDGF-BB induced the release of bFGF and sustained phosphorylation of FGFR-1 (30 minutes to 6 hours). A bFGF-neutralizing antibody inhibited PDGF-BB–mediated phosphorylation of FGFR-1, DNA synthesis, and cell proliferation. In the presence of bFGF antibody, PDGF-BB–induced early activation of ERK (0 to 60 minutes) was not affected, whereas late ERK activation (2 to 4 hours) was reduced. When FGFR-1 expression was suppressed using small interfering RNA (siRNA), ERK activation was reduced at late, but not early, time points after PDGF-BB stimulation. Addition of bFGF antibody to cells treated with siRNA to FGFR-1 had no further effect on ERK activation. Our results provide support for a novel mechanism by which PDGF-BB induces the release of bFGF and activation of FGFR-1 followed by the sustained activation of ERK and proliferation of human SMCs.