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Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt
Yasushi Mukai, … , Kenneth Walsh, James K. Liao
Yasushi Mukai, … , Kenneth Walsh, James K. Liao
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):334-343. https://doi.org/10.1172/JCI26223.
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Research Article Vascular biology

Decreased vascular lesion formation in mice with inducible endothelial-specific expression of protein kinase Akt

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Abstract

To determine whether endothelial Akt could affect vascular lesion formation, mutant mice with a constitutively active Akt transgene, which could be inducibly targeted to the vascular endothelium using the tet-off system (EC-Akt Tg mice), were generated. After withdrawal of doxycycline, EC-Akt Tg mice demonstrated increased endothelial-specific Akt activity and NO production. After blood flow cessation caused by carotid artery ligation, neointimal formation was attenuated in induced EC-Akt Tg mice compared with noninduced EC-Akt Tg mice and control littermates. To determine the role of eNOS in mediating these effects, mice were treated with Nω-nitro-L-arginine methyl ester (L-NAME). Neointimal formation was attenuated to a lesser extent in induced EC-Akt Tg mice treated with L-NAME, suggesting that some of the vascular protective effects were NO independent. Indeed, endothelial activation of Akt resulted in less EC apoptosis in ligated arteries. Immunostaining demonstrated decreased inflammatory and proliferative changes in induced EC-Akt Tg mice after vascular injury. These findings indicate that endothelial activation of Akt suppresses lesion formation via increased NO production, preservation of functional endothelial layer, and suppression of inflammatory and proliferative changes in the vascular wall. These results suggest that enhancing endothelial Akt activity alone could have therapeutic benefits after vascular injury.

Authors

Yasushi Mukai, Yoshiyuki Rikitake, Ichiro Shiojima, Sebastian Wolfrum, Minoru Satoh, Kyosuke Takeshita, Yukio Hiroi, Salvatore Salomone, Hyung-Hwan Kim, Laura E. Benjamin, Kenneth Walsh, James K. Liao

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Figure 1

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Endothelial-specific expression of inducible myrAkt transgene in EC-Akt ...
Endothelial-specific expression of inducible myrAkt transgene in EC-Akt Tg mice. (A) Western blots in primary MLEC cultures. The expression of myrAkt transgene was determined by the expression of HA tag. ECs from EC-Akt Tg mice were divided into 2 groups, with and without myrAkt gene induction. Phosphorylated forms of Akt, GSK-3, or eNOS were determined in these ECs. Each blot is representative of 3 independent experiments. (B) Endothelial expression of myrAkt in vivo. Immunostaining in carotid artery, showing HA-tag expression in the endothelial layer of an induced EC-Akt Tg mouse. Scale bar: 50 μm. (C) Immunoblots showing phosphorylation of Akt in aortae from induced EC-Akt Tg mice (left) and in primary cultures of aortic SMCs isolated from induced EC-Akt Tg mice (MASMC, right).

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