Abstract 337: G Protein-coupled Estrogen Receptor Contributes To The Vascular Effects Of Aldosterone And Type Two Diabetes-associated Vascular Dysfunction

Abstract

Aldosterone (Aldo) excess aggravates endothelial dysfunction in diabetes. Aldo exerts its effects via activation of both mineralocorticoid receptors (MR) and G protein-coupled estrogen receptors (GPER). Considering that GPER activation has beneficial effects in the vasculature, we hypothesized that GPER-mediated vascular effects of aldosterone are decreased/abrogated in diabetes. Second-order mesenteric arteries from control (B6BKS-Leprdb/+) and diabetic (db/db) female mice were incubated with 10 nM Aldo, in the presence of either vehicle (veh), the MR antagonist eplerenone (Eple, 10 μM) or the GPER antagonist G15 (1μM), and the effects on phenylephrine (Phe) vascular reactivity were determined. Aldo increased Phe maximal response (Emax, % of KCl contraction) in arteries from control (veh: 112.5±3.2 vs. Aldo: 129.1±2.8 p0.05). In control vessels, Eple did not alter Phe Emax either in the presence of Aldo or veh (p>0.05), whereas G15 abrogated Aldo-induced increase in Phe Emax (Aldo: 129.1±2.8 vs. G15+Aldo: 110.3±3.6 p<0.05). In db/db arteries, the MR and GPER antagonist decreased Phe Emax both in the presence of veh and Aldo (veh: 143.8±4.9 vs Aldo: 136.0±5.2 vs. Eple+veh: 105.4±4.8 vs. Eple+Aldo: 94.6±4.4 vs. G15+veh: 96.4±4.2 vs. G15+Aldo: 104.3±4.1 p<0.05). Arteries from diabetic mice exhibited increased ERK1/2 activation vs. control [arbitrary units (Au), 229.4±3 vs. 100.0±11.8, respectively, p<0.05]. Aldo increased ERK1/2 activation in control (Au, 99.8±0.4 vs. 272.2±58.0 p<0.05) and db/db mice (Au, 99.7±4.0 vs. 162.4±28.2 p<0.05). Eple and G15 reduced Aldo-induced ERK 1/2 activation in control arteries (p<0.05). In db/db arteries, G15 decreased ERK1/2 activation both in the presence of veh and Aldo (Au, Aldo: 162.4±28.2 vs. G15+veh: 81.1±9.1 vs. G15+aldo: 82.7±7.5 p<0.05). In summary, Aldo acutely increases contractile responses to PhE in mesenteric arteries from control animals by GPER-dependent mechanisms. In diabetic animals, both MR and GPER seem to contribute to Aldo effects in the vasculature. Contrary to our hypothesis, GPER contributes to the vascular effects of Aldo in diabetic animals as well as to diabetes-associated vascular dysfunction.