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Disruption of platelet-derived growth factor-dependent phosphatidylinositol 3-kinase and phospholipase C? 1 activity abolishes vascular smooth muscle cell proliferation and migration and attenuates neointima formation in vivo.


ABSTRACT: We tested the hypothesis whether selective blunting of platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell (VSMC) proliferation and migration is sufficient to prevent neointima formation after vascular injury.To prevent neointima formation and stent thrombosis after coronary interventions, it is essential to inhibit VSMC proliferation and migration without harming endothelial cell function. The role of PDGF-a potent mitogen and chemoattractant for VSMC that does not affect endothelial cells-for neointima formation remains controversial.To decipher the signaling pathways that control PDGF beta receptor (?PDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/?PDGFR mutants in which the binding sites for ?PDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase C? 1 [PLC?]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice.Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLC?, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLC?. These 2 signaling molecules contribute to signal relay of the ?PDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of ?PDGFR-induced PI3K and PLC? signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLC? signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury.Signaling by the activated ?PDGFR, particularly through PI3K and PLC?, is crucial for neointima formation after vascular injury. Disruption of these specific signaling pathways is sufficient to attenuate pathogenic processes such as vascular remodeling in vivo.

SUBMITTER: Caglayan E 

PROVIDER: S-EPMC3732311 | BioStudies | 2011-01-01

REPOSITORIES: biostudies

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