Cerebral vascular mitochondrial efficiency is increased by estrogen treatment

Abstract

We have previously demonstrated that estrogen, either endogenous or exogenous, increases the production of endothelial vasodilators in the cerebral vasculature. Since mitochondria are thought to play a vital role in vascular dysfunction we have investigated the impact of estrogen treatment on cerebral vascular mitochondrial electron transport and formation and metabolism of reactive oxygen species. We now show that treatment in vivo with 17beta-estradiol also modulates cerebral vascular mitochondrial function and protein expression. Mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with and without estrogen replacement for three weeks. Plasma levels achieved by estrogen replacement mimicked those seen in intact, cycling females. Estrogen receptor, ER-alpha, but not ER-beta, was detected in mitochondrial fractions, and ER-alpha protein was increased following estrogen treatment. Levels of mitochondrial cytochrome c, manganese superoxide dismutase, and subunits I and IV of complex IV also were increased in vessels from estrogen-treated rats. These findings correlated with functional increases in mitochondrial citrate synthase and complex IV activities in vessels from estrogen-treated animals. In contrast, hydrogen peroxide production, measured using succinate in vitro, was decreased in mitochondria from vessels of estrogen-treated animals. Surprisingly, PGC-1alpha expression was significantly decreased, and NRF-1 protein levels were unchanged following estrogen exposure, suggesting that estrogen acts independently of these previously defined modulators. Together, these novel findings suggest that vascular protection by estrogen is mediated, in part, by modulation of mitochondrial function resulting in greater energy producing capacity, more efficient coupling of electron transport, and decreased reactive oxygen species production.