title: Key role of PI3Kγ in monocyte chemotactic protein-1-mediated amplification of PDGF-induced aortic smooth muscle cell migration.
abstract: OBJECTIVE
  Vascular smooth muscle cell (SMC) migration within the arterial wall is a crucial event in atherogenesis and restenosis. Monocyte chemotactic protein-1/CC-chemokine receptor 2 (MCP-1/CCR2) signalling is involved in SMC migration processes but the molecular mechanisms have not been well characterized. We investigated the role of PI3Kγ in SMC migration induced by MCP-1.
  
  
  METHODS
  A pharmacological PI3Kγ inhibitor, adenovirus encoding inactive forms of PI3Kγ and genetic deletion of PI3Kγ were used to investigate PI3Kγ functions in the MCP-1 and platelet-derived growth factor (PDGF) signalling pathway and migration process in primary aortic SMC.
  
  
  RESULTS
  The γ isoform of PI3K was shown to be the major signalling molecule mediating PKB phosphorylation in MCP-1-stimulated SMC. Using a PI3Kγ inhibitor and an adenovirus encoding a dominant negative form of PI3Kγ, we demonstrated that PI3Kγ is essential for SMC migration triggered by MCP-1. PDGF receptor stimulation induced MCP-1 mRNA and protein accumulation in SMCs. Blockade of the MCP-1/CCR2 pathway or pharmacological inhibition of PI3Kγ reduced PDGF-stimulated aortic SMC migration by 50%. Thus PDGF promotes an autocrine loop involving MCP-1/CCR2 signalling which is required for PDGF-mediated SMC migration. Furthermore, SMCs isolated from PI3Kγ-deficient mice (PI3Kγ(-/-)), or mice expressing an inactive PI3Kγ (PI3Kγ(KD/KD)), migrated less than control cells in response to MCP-1 and PDGF.
  
  
  CONCLUSIONS
  PI3Kγ is essential for MCP-1-stimulated aortic SMC migration and amplifies cell migration induced by PDGF by an autocrine/paracrine loop involving MCP-1 secretion and CCR2 activation. PI3Kγ is a promising target for the treatment of aortic fibroproliferative pathologies.
authors.affiliation: INSERM, UMR, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Fougerat
authors.forename: N F
authors.initials: NF
authors.lastname: Smirnova
authors.forename: S
authors.initials: S
authors.lastname: Gayral
authors.forename: N
authors.initials: N
authors.lastname: Malet
authors.forename: E
authors.initials: E
authors.lastname: Hirsch
authors.forename: M P
authors.initials: MP
authors.lastname: Wymann
authors.forename: B
authors.initials: B
authors.lastname: Perret
authors.forename: L O
authors.initials: LO
authors.lastname: Martinez
authors.forename: M
authors.initials: M
authors.lastname: Douillon
authors.forename: M
authors.initials: M
authors.lastname: Laffargue
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D054390:Receptors, CCR2 / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D010982:Platelet-Derived Growth Factor; D054390:Receptors, CCR2; D011994:Recombinant Proteins; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt