Phosphoinositide 3-kinase γ gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions
Phosphoinositide 3-kinase γ gene knockout impairs postischemic neovascularization and endothelial progenitor cell functions
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DOI：
10.1161/atvbaha.107.145573
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发表时间：
2008-01-01
影响因子：
8.7
通讯作者：
Hirsch, Emilio
中科院分区：
文献类型：
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作者：
Madeddu, Paolo;Kraenkel, Nicolle;Hirsch, Emilio
我们评估了磷脂酰肌醇3-激酶γ（PI 3 K γ）是否在修复性新血管形成和内皮祖细胞（EPC）function.Methods和Results-Unilateral limb ischemia诱导小鼠缺乏PI 3 K γ基因（PI 3 K γ（-/-））或表达无催化活性的突变体（PI 3 K γ（KD/KD））和野生型对照（WT）。与WT相比，在导致延迟再灌注的PI 3 K γ（-/-）缺血肌肉中毛细血管化和动脉生成减少，而在PI 3 K γ（KD/KD）中保留了修复性新血管形成。在PI 3 K γ（-/-）肌肉中，内皮细胞增殖减少，凋亡增加，白细胞浸润间质空间，但缺乏WT肌肉中通常包围小动脉的cKit（+）祖细胞。PI 3 K γ由WT EPCs组成型表达，表达水平通过缺氧上调。PI 3 K γ（-/-）EPCs在增殖、存活、整合到内皮网络中以及向SDF-1迁移方面表现出缺陷。功能障碍的表型与FOXO 1的核限制、Akt和eNOS磷酸化减少以及一氧化氮（NO）产生减少有关。用NO供体预处理纠正了PI 3 K γ（-/-）EPCs的迁移缺陷。PI 3 K γ（KD/KD）EPCs显示Akt磷酸化减少，但eNOS的组成性激活和保存的增殖，存活和migration. Conclusions，我们新证明，PI 3 K γ调节血管生成，动脉生成和血管生成的机制独立于其激酶活性。
Objective-We evaluated whether phosphatidylinositol 3-kinase gamma (PI3K gamma) 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 gamma gene (PI3K gamma(-/-)) or expressing a catalytically inactive mutant (PI3K gamma(KD/KD)) and wild-type controls (WT). Capillarization and arteriogenesis were reduced in PI3K gamma(-/-) ischemic muscles resulting in delayed reperfusion compared with WT, whereas reparative neovascularization was preserved in PI3K gamma(KD/KD). In PI3K gamma(-/-) 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 gamma is constitutively expressed by WT EPCs, with expression levels being upregulated by hypoxia. PI3K gamma(-/-) 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 gamma(-/-) EPCs. PI3K gamma(KD/KD) EPCs showed reduced Akt phosphorylation, but constitutive activation of eNOS and preserved proliferation, survival, and migration.Conclusions-We newly demonstrated that PI3K gamma modulates angiogenesis, arteriogenesis, and vasculogenesis by mechanisms independent from its kinase activity.