Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions.

Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. Research Abstract Details 

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Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. Abstract Text:

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,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,

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.

Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. Publishing Authors By Initials

P Madeddu,N Kraenkel,LS Barcelos,M Siragusa,P Campagnolo,A Oikawa,A Caporali,A Herman,O Azzolino,L Barberis,A Perino,F Damilano,C Emanueli,E Hirsch,P Madeddu,N Kraenkel,LS Barcelos,M Siragusa,P Campagnolo,A Oikawa,A Caporali,A Herman,O Azzolino,L Barberis,A Perino,F Damilano,C Emanueli,E Hirsch,

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Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Arteriosclerosis, thrombosis, and vascular biology

VOLUME: 28

Page Numbers: 68-76

Journal Abbreviation: Arterioscler. Thromb. Vasc. Bi

ISSN: 1524-4636

DAY: 25

MONTH: 10

YEAR: 2007

Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. Information

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LANGUAGE: eng

NlmUniqueID: 9505803

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Grant and Affiliation Information for Phosphoinositide 3-kinase gamma gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions.

AFFILIATION: Bristol Heart Institute, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK. madeddu@yahoo.com

Country: United States

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MEDLINETA: Arterioscler Thromb Vasc Biol

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