Key role of PI3Kγ in monocyte chemotactic protein‐1‐mediated amplification of PDGF‐induced aortic smooth muscle cell migration

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACHES 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. KEY 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 (PI3KγKD/KD), migrated less than control cells in response to MCP‐1 and PDGF. CONCLUSIONS AND IMPLICATIONS 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.