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

Monica Y Lee, Ana Gamez-Mendez, Jiasheng Zhang, Zhenwu Zhuang, David J Vinyard, Jan Kraehling, Heino Velazquez, Gary W Brudvig, Themis R Kyriakides, Michael Simons, William C Sessa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)870-879
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume38
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by Grants R01 HL64793, R01 HL61371, R01 HL081190, R35 HL139945 (to W.C. Sessa), the Leducq Fondation (MIRVAD network; to W.C. Sessa), AHA MERIT Award (to W.C. Sessa), RO1 HL053793 (to M. Simons), P01 HL70295 (to M. Simons and W.C. Sessa), HL 1K99HL130581-01 to M.Y. Lee, RO1 GM072194 to T.R. Kyriakides, and the George M O’Brian Kidney Center at Yale, NIH grant P30DK079310 to H. Velazquez from the National Institutes of Health.

Publisher Copyright:
© 2018 American Heart Association, Inc.

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