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Loss of Akt1-mediated signal transduction in the vasculature is not sufficient to evoke systemic hypertension in mice.

University of Utah, 30 N 2030 E, Salt Lake City, UT, 84132

ABSTRACT

When insulin binds to its receptor in the vasculature the phosphatidylinositol 3-kinase (PI3K) and mitogen activated protein kinase (ERK 1/2) pathways are activated. PI3K activation of Akt increases endothelial nitric oxide synthase (eNOS) activity leading to vasorelaxation. Activation of ERK 1/2 stimulates endothelin-1 production and evokes vasocontraction. This led to the hypothesis that hypertension in obesity and insulin resistance results from selective impairment in PI3K signaling, with persistent ERK1/2 signaling. If this were true, we reasoned that arterial pressures should be higher in mice lacking Akt1 (i.e., Akt1–/–) in the vasculature relative to wild type (WT) controls. Insulin-mediated Akt signaling was absent in vessels from Akt1–/– vs. WT mice, but insulin-mediated ERK 1/2 phosphorylation was intact in both groups. Importantly, basal eNOS phosphorylation was similar in vessels from Akt1–/– and WT mice (n=3 per group), and did not increase in insulin-stimulated vessels. In contrast to our hypothesis, mean arterial pressures (MAP, mmHg) measured for 72 hours via telemetry indicated that no differences existed between Akt1–/– (108±5, n=4) and WT (120±9; n=4) mice. Previously we observed glucose intolerance and systemic hypertension in mice fed high fat (HF) vs. standard (Con) chow. Insulin-mediated Akt S473/T308 phosphorylation was impaired in the vasculature of HF vs. Con mice, but ERK 1/2 phosphorylation was intact. Interestingly, basal eNOS phosphorylation was virtually absent and increased marginally with insulin in vessels from HF vs. Con mice. Taken together, hypertension that exists in diet-induced obesity (i.e., HF mice) likely results from effects on eNOS phosphorylation that are independent of impaired vascular Akt-mediated signaling. AHA GIA 0655222Y

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Symons, J D Articles by Abel, E D PubMed Articles by Symons, J D Articles by Abel, E D