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J. Biol. Chem., Vol. 279, Issue 40, 42221-42229, October 1, 2004

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Proliferation of Neointimal Smooth Muscle Cells after Arterial Injury

DEPENDENCE ON INTERACTIONS BETWEEN FIBROBLAST GROWTH FACTOR RECEPTOR-2 AND FIBROBLAST GROWTH FACTOR-9^*

Alex Agrotis, Peter Kanellakis, Gina Kostolias, Giovanna Di Vitto, Chen Wei, Ross Hannan¶, Garry Jennings, and Alex Bobik||

From the Cell Biology Laboratory, Baker Heart Research Institute, St. Kilda Road Central, P. O. Box 6492, Melbourne 8008, Victoria, Australia, the ^||Alfred Hospital, Commercial Road, Melbourne, Victoria 3181, Australia, and the ^¶Growth Control Laboratory, Peter MacCallum Cancer Institute, St. Andrews Place, East Melbourne, Victoria 3002, Australia

The growth factor signaling mechanisms responsible for neointimal smooth muscle cell (SMC) proliferation and accumulation, a characteristic feature of many vascular pathologies that can lead to restenosis after angioplasty, remain to be identified. Here, we examined the contribution of fibroblast growth factor receptors (FGFRs) 2 and 3 as well as novel fibroblast growth factors (FGFs) to such proliferation. Balloon catheter injury to the rat carotid artery stimulated the expression of two distinctly spliced FGFR-2 isoforms, differing only by the presence or absence of the acidic box, and two distinctly spliced FGFR-3 isoforms containing the acidic box and differing only by the presence of either the IIIb or IIIc exon. Post-injury arterial administration of recombinant adenoviruses expressing dominant negative mutant forms of these FGFRs were used to assess the roles of the endogenous FGFR isoforms in neointimal SMC proliferation. Dominant negative FGFR-2 containing the acidic box inhibited such proliferation by 40%, whereas the dominant negative FGFR-3 forms had little effect. Expression of FGF-9, known to be capable of binding to all four neointimal FGFR-2/-3 isoforms, was abundant within the neointima. FGF-9 markedly stimulated both the proliferation of neointimal SMCs and the activation of extracellular signal-related kinases 1/2, effects which were abrogated by the administration of antisense FGF-9 oligonucleotides to injured arteries and the expression of the dominant negative FGFR-2 adenovirus in cultured neointimal SMCs. These studies demonstrate that, although multiple FGFRs are induced in neointimal SMCs following arterial injury, specific interactions between distinctly spliced FGFR-2 isoforms and FGF-9 contribute to the proliferation of these SMCs.

Received for publication, July 19, 2004

^* This work was supported by a Program Grant from the National Health and Medical Research Council of Australia and a grant-in-aid from the National Heart Foundation of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 61-3-8532-1189; Fax: 61-3-8532-1100; E-mail: alex.agrotis{at}baker.edu.au.

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