Phosphoinositide 3-Kinase γ Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions

Abstract
Objective— We evaluated whether phosphatidylinositol 3-kinase γ (PI3Kγ) plays a role in reparative neovascularization and endothelial progenitor cell (EPC) function. Methods and Results— Unilateral limb ischemia was induced in mice lacking the PI3Kγ gene (PI3Kγ−/−) or expressing a catalytically inactive mutant (PI3KγKD/KD) and wild-type controls (WT). Capillarization and arteriogenesis were reduced in PI3Kγ−/− ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3KγKD/KD. In PI3Kγ−/− muscles, endothelial cell proliferation was reduced, apoptosis was increased, and interstitial space was infiltrated with leukocytes but lacked cKit+ progenitor cells that in WT muscles typically surrounded arterioles. PI3Kγ is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia. PI3Kγ−/− EPCs showed a defect in proliferation, survival, integration into endothelial networks, and migration toward SDF-1. The dysfunctiona... We demonstrated that PI3Kγ is fundamental for reparative neovascularization and EPC function. PI3Kγ is upregulated in ischemic limb muscles and hypoxic EPCs. After limb ischemia, PI3Kγ-deficient mice show impaired revascularization and blood flow recovery, attributable to reduced EC proliferation and enhanced apoptosis. PI3Kγ deficiency impairs EPC growth, survival, migration, and adhesion.