Phosphoinositide 3-kinase Gamma Gene Knockout Impairs Postischemic Neovascularization and Endothelial Progenitor Cell Functions

Overview

Journal Arterioscler Thromb Vasc Biol

Date 2007 Oct 27

PMID 17962628

Citations 33

Authors

Paolo Madeddu

Nicolle Kraenkel

Luciola S Barcelos

Mauro Siragusa

Paola Campagnolo

Atsuhiko Oikawa

Andrea Caporali

Andrew Herman

Ornella Azzolino

Laura Barberis

Alessia Perino

Federico Damilano

Costanza Emanueli

Emilio Hirsch

Affiliations

Soon will be listed here.

Abstract

Objective: We evaluated whether phosphatidylinositol 3-kinase gamma (PI3Kgamma) plays a role in reparative neovascularization and endothelial progenitor cell (EPC) function.

Methods And Results: Unilateral limb ischemia was induced in mice lacking the PI3Kgamma gene (PI3Kgamma-/-) or expressing a catalytically inactive mutant (PI3Kgamma(KD/KD)) and wild-type controls (WT). Capillarization and arteriogenesis were reduced in PI3Kgamma-/- ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3Kgamma(KD/KD). In PI3Kgamma-/- 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. PI3Kgamma is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia. PI3Kgamma-/- 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 PI3Kgamma-/- EPCs. PI3Kgamma(KD/KD) EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration.

Conclusions: We newly demonstrated that PI3Kgamma modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.

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