This Article Full Text Full Text (PDF) All Versions of this Article: 96/2/172    most recent 01.RES.0000154595.87608.dbv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Millette, E. Articles by Clowes, A. W. Search for Related Content PubMed PubMed Citation Articles by Millette, E. Articles by Clowes, A. W. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB HEPARIN Related Collections Mechanism of atherosclerosis/growth factors Cell signalling/signal transduction Smooth muscle proliferation and differentiation

(Circulation Research. 2005;96:172.)
© 2005 American Heart Association, Inc.

Molecular Medicine

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

Esther Millette, Bernhard H. Rauch, Olivier Defawe, Richard D. Kenagy, Guenter Daum, Alexander W. Clowes

From the University of Washington School of Medicine, Department of Surgery, Seattle, Wash.

Correspondence to Esther Millette, PhD, University of Washington School of Medicine, Department of Surgery, Box 356410, 1959 NE Pacific St, Seattle, WA 98195-6410. E-mail millette{at}u.washington.edu

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.

Key Words: platelet-derived growth factor • bFGF release • FGFR-1 • ERK • Akt

This article has been cited by other articles:

				K. Borensztajn, J. Stiekema, S. Nijmeijer, P. H. Reitsma, M. P. Peppelenbosch, and C. A. Spek Factor Xa Stimulates Proinflammatory and Profibrotic Responses in Fibroblasts via Protease-Activated Receptor-2 Activation Am. J. Pathol., February 1, 2008; 172(2): 309 - 320. [Abstract] [Full Text] [PDF]

				B. H. Rauch, G. A. Scholz, D. Baumgartel-Allekotte, P. Censarek, J. W. Fischer, A.-A. Weber, and K. Schror Cholesterol Enhances Thrombin-Induced Release of Fibroblast Growth Factor-2 in Human Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): e20 - e25. [Abstract] [Full Text] [PDF]

				T. Nomiyama, T. Nakamachi, F. Gizard, E. B. Heywood, K. L. Jones, N. Ohkura, R. Kawamori, O. M. Conneely, and D. Bruemmer The NR4A Orphan Nuclear Receptor NOR1 Is Induced by Platelet-derived Growth Factor and Mediates Vascular Smooth Muscle Cell Proliferation J. Biol. Chem., November 3, 2006; 281(44): 33467 - 33476. [Abstract] [Full Text] [PDF]

				O. Thaunat, L. Louedec, J. Dai, F. Bellier, E. Groyer, S. Delignat, A.-T. Gaston, G. Caligiuri, E. Joly, D. Plissonnier, et al. Direct and Indirect Effects of Alloantibodies Link Neointimal and Medial Remodeling in Graft Arteriosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2359 - 2365. [Abstract] [Full Text] [PDF]

				T. Raj, P. Kanellakis, G. Pomilio, G. Jennings, A. Bobik, and A. Agrotis Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1845 - 1851. [Abstract] [Full Text] [PDF]

				T. Khomenko, S. Szabo, X. Deng, M. R. Jadus, H. Ishikawa, K. Osapay, Z. Sandor, and L. Chen Suppression of early growth response factor-1 with egr-1 antisense oligodeoxynucleotide aggravates experimental duodenal ulcers Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1211 - G1218. [Abstract] [Full Text] [PDF]

				D. Faraone, M. S. Aguzzi, G. Ragone, K. Russo, M. C. Capogrossi, and A. Facchiano Heterodimerization of FGF-receptor 1 and PDGF-receptor-{alpha}: a novel mechanism underlying the inhibitory effect of PDGF-BB on FGF-2 in human cells Blood, March 1, 2006; 107(5): 1896 - 1902. [Abstract] [Full Text] [PDF]

				R. P. Jankov, C. Kantores, R. Belcastro, S. Yi, R. A. Ridsdale, M. Post, and A. K. Tanswell A role for platelet-derived growth factor {beta}-receptor in a newborn rat model of endothelin-mediated pulmonary vascular remodeling Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1162 - L1170. [Abstract] [Full Text] [PDF]