Abstract
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.
Highlights
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
fibroblast growth factor receptors (FGFRs) Expression in Proliferating SMCs of the Neointima— Because FGFRs bind fibroblast growth factors (FGFs) family members with varying affinities, and alternative hnRNA splicing leads to receptor isoforms that possess unique FGF binding properties [14, 17], we initially investigated the expression of two FGFRs, FGFR-2 and FGFR-3, in the rapidly proliferating SMCs within the growing neointima of healing rat carotid arteries injured with an inflated balloon catheter
An involvement of FGF:FGFR signaling in intimal/neointimal SMC proliferation has been suggested, based on studies demonstrating the presence of FGFR-1 in healing arteries [11] and the expression of FGFR-1, FGFR-2, and FGFR-3 in atherosclerotic arteries [12, 13]
Summary
DEPENDENCE ON INTERACTIONS BETWEEN FIBROBLAST GROWTH FACTOR RECEPTOR-2 AND FIBROBLAST GROWTH FACTOR-9*. One such splicing event results in a deletion of the exon encoding the amino-terminal Ig-like domain (domain I), resulting in a shorter, two-Ig-like domain isoform of the receptor [15]; such shorter FGFRs (“-forms”) frequently have higher affinities for some FGFs than do the corresponding longer three-Ig-like domain FGFRs (“␣-forms”) and, in some instances, have been associated with tumor progression [16] Another splicing event that can dramatically alter the FGF binding ability of FGFR-1, blast growth factor; FGFR, fibroblast growth factor receptor; BrdUrd, bromodeoxyuridine; RT, reverse transcription; DN, dominant negative; GFP, green fluorescent protein; ERK, extracellular signal-related kinase. These findings, for the first time, demonstrate a major regulatory role for an FGFR2-IIIc/FGF-9 interaction in the stimulation of neointimal SMC proliferation in the injured arterial wall
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