Proliferation of neointimal smooth muscle cells after arterial injury. Dependence on interactions between fibroblast growth factor receptor-2 and fibroblast growth factor-9.
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.
Agrotis
Alex
A
Cell Biology Laboratory, Baker Heart Research Institute, St. Kilda Road Central, P. O. Box 6492, Melbourne 8008, Victoria, Australia. alex.agrotis@baker.edu.au
Kanellakis
Peter
P
Kostolias
Gina
G
Di Vitto
Giovanna
G
Wei
Chen
C
Hannan
Ross
R
Jennings
Garry
G
Bobik
Alex
A
D000818:Animals; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D020033:Protein Isoforms / Q000032:analysis / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D017539:Tunica Intima / Q000166:cytology
C496461:Fgf9 protein, rat; D051525:Fibroblast Growth Factor 9; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496356:Fgfr2 protein, rat; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D020928:Mitogen-Activated Protein Kinases