The angiotensin II type 2 receptor promotes perivascular adipose tissue-dependent dilation in type 2 diabetic female mice and contraction in healthy mice

Abstract

Diabetes mellitus is associated with severe cardiovascular disorders involving the renin-angiotensin system, mainly through angiotensin II type 1 receptor (AT1R) activation. Although the angiotensin type 2 receptor (AT2R) opposes the effects of AT1R, with vasodilator and anti-trophic properties, its role in diabetes remains debatable. However, AT2R expression level is activated by estrogens and is involved in adipose tissue maturation and in vasodilatation in type 1 diabetes. We investigated the role of AT2R in perivascular adipose tissue (PVAT)-dependent tone in the aorta in a model of type 2 diabetes in female mice with AT2R(AT2R+/+) or without(AT2R−/−). We used 3 month-old female AT2R+/+ and AT2R−/− mice fed a diabetogenic diet in order to induce type 2 diabetes after 4 months. Mice were intact or ovariectomized. Arteries were isolated for in vitro study of vascular reactivity and left with or without PVAT. In AT2R+/+ mice, in the presence of PVAT, phenylephrine-mediated contraction was increased, but PVAT did not affect endothelium dependent (acetylcholine) and independent (sodium nitroprusside)-relaxation. This effect of PVAT was abolished after ovariectomy. PVAT-dependent contraction was also absent in AT2R−/− mice. On the other hand, in type 2 diabetic mice, PVAT was associated with a reduced vasoconstriction and increased vasodilation. In these diabetic mice, PVAT-dependent relaxation was abolished in AT2R−/− mice whereas it was not affected by ovariectomy. Thus, PVAT, in diabetic female mice, opposes vasoconstriction through a mechanism involving AT2R. Therefore AT2R might represent a new therapeutic target in type 2 diabetes in females.