Phosphoinositide 3-kinase gamma 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 journalArticlepeer-review

Abstract / Description of output

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 (PI3KγKD/KD) 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 PI3KγKD/KD. 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. PI3KγKD/KD 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
Issue number1
Publication statusPublished - Jan 2008

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Class Ib Phosphatidylinositol 3-Kinase
  • Disease Models, Animal
  • Endothelial Cells
  • Extremities
  • Ischemia
  • Isoenzymes
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth
  • Neovascularization, Physiologic
  • Phosphatidylinositol 3-Kinases
  • Stem Cells
  • Transplants


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