17ß-estradiol antagonizes the down-regulation of ERα/NOS-3 signaling in vascular endothelial dysfunction of female diabetic rats.

Abstract

Previous studies indicated that estrogen could improve endothelial function. However, whether estrogen protects vascular complications of diabetes has yet to be clarified. The study was designed to investigate the action of 17ß-estradiol on vascular endothelium in streptozotocin (STZ)-induced diabetic rats. Ovariectomized female Sprague-Dawley rats were administered with streptozotocin to produce an ovariectomized-diabetic (OVS) model which manifested as dysfunction of aortic dilation and contraction ability. Meanwhile, OVS animals with 17ß-estradiol supplementation significantly improved aortic function. Accordingly, nitric oxide synthase-3 (NOS-3), Akt, PI3K and estrogen receptor α (ERα) protein expression in aorta declined in the OVS group. Such effects were partially restored by estrogen replacement. The presence of 17ß-estradiol similarly counteracted the reduction of cyclic guanosine monophosphate (cGMP), the enhanced expression of inducible NOS (NOS-2) and NO metabolites (nitrite and nitrate), as well as the increase of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1), which is an index of arterial compliance. 17ß-estradiol could also decrease ROS production in vascular endothelium. In EA hy 926 cells we found that ER antagonist, wortmannin and Akt inhibitor could block improvement effects of 17ß-estradiol. These results strongly suggest that functional impairment of the ERα/NOS-3 signaling network in OVS animals was partially restored by 17ß-estradiol administration, which provides experimental support for estrogen recruitment to improve vascular outcomes in female diabetes after endogenous hormone depletion.