on October 25, 2007
Published online before print October 25, 2007, doi: 10.1161/ATVBAHA.107.145573
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Submitted on April 16, 2007
Accepted on September 14, 2007
Phosphoinositide 3-Kinase 
Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions
Paolo Madeddu *;
From the Bristol Heart Institute (P.M., M.K., L.S.B., M.S., P.C., A.O., A.C., C.E.) and Cellular and Molecular Medicine (A.H.), University of Bristol, UK; the Molecular Biotechnology Center (O.A., L.B., A.P., P.D., E.H.), University of Turin, Italy; and INBB (N.K., A.O.), Osilo/Rome, Italy.
* To whom correspondence should be addressed. E-mail: madeddu{at}yahoo.com.
Objective—We evaluated whether phosphatidylinositol 3-kinase 
(PI3K) plays a role in reparative neovascularization and endothelial progenitor cell (EPC) function.
Methods and Results—Unilateral limb ischemia was induced in mice lacking the PI3K gene (PI3K-/-) or expressing a catalytically inactive mutant (PI3KkDa/kDa) and wild-type controls (WT). Capillarization and arteriogenesis were reduced in PI3K-/- ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3KkDa/kDa. In PI3K-/- 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. PI3K is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia. PI3K-/- EPCs showed a defect in proliferation, survival, integration into endothelial networks, and migration toward SDF-1. The dysfunctional phenotype was associated with nuclear constraining of FOXO1, reduced Akt and eNOS phosphorylation, and decreased nitric oxide (NO) production. Pretreatment with an NO donor corrected the migratory defect of PI3K-/-EPCs. PI3KkDa/kDa EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration.
Conclusions—We newly demonstrated that PI3K modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.
Key words: limb ischemia • angiogenesis • vasculogenesis • endothelial progenitor cells • migration
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