title: 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.
abstract: OBJECTIVE
  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 (βPDGFR)-driven VSMC proliferation and migration, we characterized 2 panels of chimeric CSF1R/βPDGFR mutants in which the binding sites for βPDGFR-associated signaling molecules (Src, phosphatidylinositol 3-kinase [PI3K], GTPase activating protein of ras, SHP-2, phospholipase Cγ 1 [PLCγ]) 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 PLCγ, whereas PDGF-dependent cell cycle progression is exclusively mediated by PI3K and PLCγ. These 2 signaling molecules contribute to signal relay of the βPDGFR by differentially regulating cyclin D1 and p27(kip1). Blunting of βPDGFR-induced PI3K and PLCγ signaling by a combination mutant (F3) completely abolished the mitogenic and chemotactic response to PDGF. Disruption of PDGF-dependent PI3K and PLCγ signaling in mice expressing the F3 receptor led to a profound reduction of neointima formation after balloon injury.
  
  
  CONCLUSIONS
  Signaling by the activated βPDGFR, particularly through PI3K and PLCγ, 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.
authors.affiliation: Klinik III für Innere Medizin, Universität zu Köln, Köln, Germany; Center for Molecular Medicine Cologne, Universität zu Köln, Köln, Germany.
authors.forename: Evren
authors.initials: E
authors.lastname: Caglayan
authors.forename: Marius
authors.initials: M
authors.lastname: Vantler
authors.forename: Olli
authors.initials: O
authors.lastname: Leppänen
authors.forename: Felix
authors.initials: F
authors.lastname: Gerhardt
authors.forename: Lenard
authors.initials: L
authors.lastname: Mustafov
authors.forename: Henrik
authors.initials: H
authors.lastname: Ten Freyhaus
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.forename: Wolfram H
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tallquist
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology*; D058426:Neointima / Q000517:prevention & control*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D010982:Platelet-Derived Growth Factor; D058539:Phosphatidylinositol 3-Kinase; D051966:Phospholipase C gamma