Akt/eNOS pathway activation in endothelium-dependent relaxation is preserved in aortas from female, but not from male, type 2 diabetic mice.

Abstract Cardiovascular problems are major causes of morbidity and mortality, the main problems being coronary artery disease and atherosclerosis, in type 2 diabetes mellitus. However, female gender is a protective factor in the development of, for example, atherosclerosis and hypertension. Our aim was to investigate possible gender differences in the activation of Akt/eNOS signaling in aortas from a mouse type 2 diabetic model. Nonfasting plasma glucose was significantly above control in the diabetic mice (both males and females). Plasma insulin was not different between the age-matched controls and the diabetic mice (of either gender). In diabetic males (vs male controls and/or diabetic females): (a) systemic blood pressure was elevated, (b) the clonidine- and insulin-induced Akt-dependent aortic relaxations were impaired, but the ACh-induced Akt-independent and SNP-induced endothelium-independent aortic relaxations were not, (c) Akt and eNOS expression levels were lower, (d) both Akt phosphorylation at Ser 473 and eNOS phosphorylation at Ser 1177 in the aorta were lower under clonidine- or insulin-stimulation, but not under ACh-stimulation. These results suggest that in mice: (i) endothelial functions mediated via the Akt/eNOS pathway are abrogated in type 2 diabetes only in males and (ii) in females (vs males), eNOS expression is elevated and the endothelium resists dysfunction.