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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-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Caglayan Evren E Vantler Marius M Leppänen Olli O Gerhardt Felix F Mustafov Lenard L Ten Freyhaus Henrik H Kappert Kai K Odenthal Margarete M Zimmermann Wolfram H WH Tallquist Michelle D MD Rosenkranz Stephan S

Journal of the American College of Cardiology 20110601 25

<h4>Objectives</h4>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.<h4>Background</h4>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 chemoa ...[more]

PMID: 21679854

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Project description:ObjectivePlasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.Approach and resultsPAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury.ConclusionsPAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.

Dataset Information

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.

Publications

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

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