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

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