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

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

Research output: Contribution to journalArticle

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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 (PI3Kγ) 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 PI3Kγ. 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 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 PI3Kγ EPCs. PI3Kγ EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration. CONCLUSIONS - We newly demonstrated that PI3Kγ modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.

Original languageEnglish
Pages (from-to)68-76
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2008

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Phosphatidylinositol 3-Kinase
Gene Knockout Techniques
1-Phosphatidylinositol 4-Kinase
Endothelial Progenitor Cells
Phosphorylation
Muscles
Nitric Oxide Donors
Arterioles
Muscle Cells
Reperfusion

Keywords

  • Angiogenesis
  • Endothelial progenitor cells
  • Limb ischemia
  • Migration
  • Vasculogenesis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Phosphoinositide 3-kinase γ gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. / Madeddu, Paolo; Kraenkel, Nicolle; Barcelos, Luciola S.; Siragusa, Mauro; Campagnolo, Paola; Oikawa, Atsuhiko; Caporali, Andrea; Herman, Andrew; Azzolino, Ornella; Barberis, Laura; Perino, Alessia; Damilano, Federico; Emanueli, Costanza; Hirsch, Emilio.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 28, No. 1, 01.2008, p. 68-76.

Research output: Contribution to journalArticle

Madeddu, P, Kraenkel, N, Barcelos, LS, Siragusa, M, Campagnolo, P, Oikawa, A, Caporali, A, Herman, A, Azzolino, O, Barberis, L, Perino, A, Damilano, F, Emanueli, C & Hirsch, E 2008, 'Phosphoinositide 3-kinase γ gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 1, pp. 68-76. https://doi.org/10.1161/ATVBAHA.107.145573
Madeddu, Paolo ; Kraenkel, Nicolle ; Barcelos, Luciola S. ; Siragusa, Mauro ; Campagnolo, Paola ; Oikawa, Atsuhiko ; Caporali, Andrea ; Herman, Andrew ; Azzolino, Ornella ; Barberis, Laura ; Perino, Alessia ; Damilano, Federico ; Emanueli, Costanza ; Hirsch, Emilio. / Phosphoinositide 3-kinase γ gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2008 ; Vol. 28, No. 1. pp. 68-76.
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AU - Kraenkel, Nicolle

AU - Barcelos, Luciola S.

AU - Siragusa, Mauro

AU - Campagnolo, Paola

AU - Oikawa, Atsuhiko

AU - Caporali, Andrea

AU - Herman, Andrew

AU - Azzolino, Ornella

AU - Barberis, Laura

AU - Perino, Alessia

AU - Damilano, Federico

AU - Emanueli, Costanza

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N2 - 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 (PI3Kγ) 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 PI3Kγ. 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 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 PI3Kγ EPCs. PI3Kγ EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration. CONCLUSIONS - We newly demonstrated that PI3Kγ modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.

AB - 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 (PI3Kγ) 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 PI3Kγ. 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 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 PI3Kγ EPCs. PI3Kγ EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration. CONCLUSIONS - We newly demonstrated that PI3Kγ modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.

KW - Angiogenesis

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