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Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):870-879. doi: 10.1161/ATVBAHA.118.310748. Epub 2018 Feb 15.

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

Author information

1
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.).
2
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.). william.sessa@yale.edu.

Abstract

OBJECTIVE:

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.

APPROACH AND RESULTS:

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.

CONCLUSIONS:

Endothelial Akt1 signaling is necessary for ischemic resolution post-injury and likely reflects the consequence of NO insufficiency critical for vascular repair.

KEYWORDS:

blood pressure; endothelial cell; hindlimb; homeostasis; phosphorylation

PMID:
29449333
PMCID:
PMC6503971
DOI:
10.1161/ATVBAHA.118.310748
[Indexed for MEDLINE]
Free PMC Article

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