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Department of Pharmacology, College of Medicine, University of California, Irvine, Irvine, California (C.S., S.P.D., D.N.K.); Department of Pediatrics, College of Medicine, University of California, Irvine, Irvine, California (V.P.); Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, Irvine, California (V.P.)
We report here that estrogen (E2) modulates mitochondrial function in the vasculature. Mitochondrial dysfunction is implicated in the etiology of vascular disease; thus, vasoprotection by estrogen may involve hormonal effects on the mitochondria. To test this hypothesis, mitochondria were isolated from cerebral blood vessels obtained from ovariectomized female rats, with or without E2 replacement. Estrogen receptor-
(ER-) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E2 treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-, cytochrome c, subunit IV of complex IV, and manganese superoxide dismutase, all encoded in the nuclear genome, and subunit I of complex IV, encoded in the mitochondrial genome. Levels of glutathione peroxidase-1 and catalase, however, were not affected. Functional assays of mitochondrial citrate synthase and complex IV, key rate-limiting steps in energy production, showed that E2 treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E2-treated animals. In vitro incubation of cerebral vessels with 10 nM 17
-estradiol for 18 h also elevated levels of mitochondrial cytochrome c. This effect was blocked by the estrogen receptor antagonist fulvestrant (ICI-182,780, Faslodex) but was unaffected by inhibitors of nitric-oxide synthase or phosphoinositide-3-kinase. Nuclear respiratory factor-1 protein, a primary regulator of nuclear gene-encoded mitochondrial genes, was significantly increased by long-term estrogen treatment in vivo. In summary, these novel findings suggest that vascular protection by E2 is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.
Address correspondence to: Dr. Vincent Procaccio, Center for Molecular and Mitochondrial Medicine and Genetics, University of California Irvine, Irvine, CA 92697. E-mail: vproca{at}uci.edu
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