The estrogen-mediated vasculoprotective effect has been widely reported in many animal studies, although the clinical trials are controversial and the detailed mechanisms remain unclear. In this study, we focused on the molecular mechanism and consequence of 17 beta-estradiol (E2)-induced ERR alpha (estrogen-related receptor alpha) expression in endothelium and its potential beneficial effects on vascular function. The human aorta endothelial cells were used to identify the detailed molecular mechanism and consequences for E2-induced ERR alpha expression through estrogen receptors (ER), where ER alpha responses E2-induced ERR alpha activation, and ER beta responses basal ERR alpha expression. E2-induced ERR alpha expression increases fatty acid uptake/oxidation with increased mitochondrial replication, ATP generation and attenuated reactive oxygen species (ROS) formation. We have obtained further in vivo proof from high-fat diet mice that the lentivirus-carried endothelium-specific delivery of ERR alpha expression on the vascular wall normalizes E2 deficiency-induced increased plasma lipids with ameliorated vascular damage. ERR alpha knockdown worsens the problem, and the E2 could only partly restore this effect. This is the first time we report the detailed mechanism with direct evidence that E2-induced ERR alpha expression modulates the fatty acid metabolism and reduces the circulating lipids through endothelium. We conclude that E2-induced ERR alpha expression in endothelium plays an important role for the E2-induced vasculoprotective effect. (C) 2015 Elsevier Ltd. All rights reserved.