Abstract 348: Genetic Disruption of the PI3 Kinase {gamma} Impairs Reparative Neovascularization of Ischemic Limb Muscles and Depresses the Functionality of Bone Marrow-Derived Progenitor Cells

The PI3 Kinase γ (PI3Kγ), which lays upstream to Akt, modulates the directed migration of leukocytes and the interaction between leukocytes and vascular cells. The present study aimed to test the role of PI3Kγ in reparative neovascularization of ischemic limb muscles. PI3Kγ knockout (KO) and wild type (WT) mice (n=10 per group) were submitted to unilateral limb ischemia. Blood flow (BF) recovery was measured by laser Doppler flowmetry and muscular capillarization by histology. The expression of PI3Kγ, total and phosho Erk1/2 (pErk1/2) and total and Ser473-phospho Akt (Akt) in muscles was analyzed by western blot. In addition, endothelial progenitor cells (EPC) were enriched from bone marrow mononuclear cells and then studied in vitro to determine the impact of PI3Kγ deletion on survival, migration toward SDF-1, and pAkt content and localization. BF recovery was delayed in KO (ischemic to contralateral ratio at 2 weeks: 0.64±0.05 vs. 0.86±0.04 in WT, P 2 in contralateral normoperfused muscles, P 2 in contralateral, P=N.S.), abnormal leukocyte infiltration, increased myocyte apoptosis, and reduced phospho to total Akt ratio (P