From the Vascular Biology and Therapeutics Program, Department of Pharmacology (M.Y.L., A.G.-M., J.K., W.C.S.), Vascular Biology and Therapeutics Program, Department of Pathology (T.R.K.), and Department of Cell Biology (M.S.), Yale University School of Medicine, New Haven, CT; Department of Internal Medicine, Section of Cardiovascular Medicine, Yale Cardiovascular Research Center, New Haven, CT (J.Z., Z.Z., M.S.); Department of Chemistry, Yale University, New Haven, CT (D.J.V., G.W.B.); and Department of Internal Medicine, VA Connecticut Healthcare System, West Haven, CT (H.V.).
Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):870-879. doi: 10.1161/ATVBAHA.118.310748. Epub 2018 Feb 15.
The importance of PI3K/Akt signaling in the vasculature has been demonstrated in several models, as global loss of Akt1 results in impaired postnatal ischemia- and VEGF-induced angiogenesis. The ubiquitous expression of Akt1, however, raises the possibility of cell-type-dependent Akt1-driven actions, thereby necessitating tissue-specific characterization.
Herein, we used an inducible, endothelial-specific Akt1-deleted adult mouse model (Akt1iECKO) to characterize the endothelial cell autonomous functions of Akt1 in the vascular system. Endothelial-targeted ablation of Akt1 reduces eNOS (endothelial nitric oxide synthase) phosphorylation and promotes both increased vascular contractility in isolated vessels and elevated diastolic blood pressures throughout the diurnal cycle in vivo. Furthermore, Akt1iECKO mice subject to the hindlimb ischemia model display impaired blood flow and decreased arteriogenesis.
Endothelial Akt1 signaling is necessary for ischemic resolution post-injury and likely reflects the consequence of NO insufficiency critical for vascular repair.
在多种模型中已经证明了 PI3K/Akt 信号通路在血管中的重要性，因为 Akt1 的全局缺失会导致出生后缺血和 VEGF 诱导的血管生成受损。然而，Akt1 的普遍表达提出了细胞类型依赖性 Akt1 驱动作用的可能性，因此需要进行组织特异性表征。
在此，我们使用了一种可诱导的、内皮特异性 Akt1 缺失的成年小鼠模型（Akt1iECKO）来表征 Akt1 在血管系统中的内皮细胞自主功能。内皮靶向敲除 Akt1 会降低 eNOS（内皮型一氧化氮合酶）的磷酸化，并促进分离血管中的血管收缩性增加和体内昼夜周期中的舒张压升高。此外，接受后肢缺血模型的 Akt1iECKO 小鼠显示血流受损和动脉生成减少。
内皮细胞 Akt1 信号通路对于损伤后的缺血缓解是必要的，这可能反映了对血管修复至关重要的 NO 不足的后果。
