Disruption of Platelet-Derived Growth Factor-Dependent Phosphatidylinositol 3-Kinase and Phospholipase C gamma 1 Activity Abolishes Vascular Smooth Muscle Cell Proliferation and Migration and Attenuates Neointima Formation In Vivo

Abstract

Objectives 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. Background 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. Methods To decipher the signaling pathways that control PDGF beta receptor (beta PDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/beta PDGFR mutants in which the binding sites for beta PDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase C gamma 1 [PLC gamma]) were individually mutated. Based on in vitro results, the importance of PDGF-initiated signals for neointima formation was investigated in genetically modified mice. Results Our results indicate that the chemotactic response to PDGF requires the activation of Src, PI3K, and PLC gamma, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLC gamma. These 2 signaling molecules contribute to signal relay of the beta PDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of beta PDGFR-induced PI3K and PLC gamma signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLC gamma signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury. Conclusions Signaling by the activated beta PDGFR, particularly through PI3K and PLC gamma, 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. (J Am Coll Cardiol 2011;57:2527-38) (C) 2011 by the American College of Cardiology Foundation