Research article summary (published 27 Dec 2004):

Platelet-derived growth factor-BB-induced human smooth muscle cell proliferation depends on basic FGF release and FGFR-1 activation.

Full Abstract

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.

Author information

Author/s: Millette, Esther (E); Rauch, Bernhard H (BH); Defawe, Olivier (O); Kenagy, Richard D (RD); Daum, Guenter (G); Clowes, Alexander W (AW);

Affiliation: University of Washington School of Medicine, Department of Surgery, Box 356410, 1959 NE Pacific St, Seattle, WA 98195-6410, USA. millette(-atsign-)u.washington.edu

Grants: HL-18645 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Journal: Circulation research (Circ Res), published in United States. (Language: eng)

Reference: 2005-Feb; vol 96 (issue 2) : pp 172-9

Dates: Created 2005/02/04; Completed 2005/08/02; Revised 2007/11/15;

PMID: 15625285, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Aorta, Abdominal Cell Division - drug effects Cell Movement - drug effects Cells, Cultured - drug effects; metabolism Chromones - pharmacology DNA Replication - drug effects Enzyme Activation - drug effects Fibroblast Growth Factor 2 - pharmacology; physiology; secretion Flavonoids - pharmacology Heparin - pharmacology Humans Indoles - pharmacology MAP Kinase Kinase 1 - metabolism MAP Kinase Kinase 2 - metabolism Maleimides - pharmacology Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism

Mitogen-Activated Protein Kinase 3 - metabolism Morpholines - pharmacology Muscle, Smooth, Vascular - cytology; drug effects Myocytes, Smooth Muscle - drug effects; 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 RNA, Small Interfering - pharmacology Receptor Protein-Tyrosine Kinases - genetics; physiology Receptor, Fibroblast Growth Factor, Type 1 Receptors, Fibroblast Growth Factor - genetics; physiology Recombinant Proteins - pharmacology Tyrphostins - pharmacology

Associated Chemicals: Chromones (0) ; Flavonoids (0) ; Indoles (0) ; Maleimides (0) ; Morpholines (0) ; PD 98059 (0) ; Platelet-Derived Growth Factor (0) ; Protein Kinase Inhibitors (0) ; Proto-Oncogene Proteins (0) ; RNA, Small Interfering (0) ; Receptors, Fibroblast Growth Factor (0) ; Recombinant Proteins (0) ; Tyrphostins (0) ; platelet-derived growth factor A (0) ; platelet-derived growth factor BB (0) ; Fibroblast Growth Factor 2 (103107-01-3) ; bisindolylmaleimide I (133052-90-1) ; 6,7-dimethoxy-3-phenylquinoxaline (146535-11-7) ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (154447-36-6) ; Heparin (9005-49-6) ; MAP Kinase Kinase 1 (EC 2.7.1.-) ; MAP Kinase Kinase 2 (EC 2.7.1.-) ; MAP2K1 protein, human (EC 2.7.1.-) ; MAP2K2 protein, human (EC 2.7.1.-) ; FGFR1 protein, human (EC 2.7.1.112) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; Receptor, Fibroblast Growth Factor, Type 1 (EC 2.7.1.112) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.1.37) ; Proto-Oncogene Proteins c-akt (EC 2.7.1.37) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)

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