Estrogen increases mitochondrial efficiency and reduces oxidative stress in cerebral blood vessels.
We report here that estrogen (E(2)) 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 E(2) replacement. Estrogen receptor-alpha (ER-alpha) was detected in mitochondria by immunoblot and confocal imaging of intact vessels. E(2) treatment in vivo increased the levels of specific proteins in cerebrovascular mitochondria, such as ER-alpha, 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 E(2) treatment increased enzyme activity. In contrast, mitochondrial production of hydrogen peroxide was decreased in vessels from E(2)-treated animals. In vitro incubation of cerebral vessels with 10 nM 17beta-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 E(2) is mediated, in part, by modulation of mitochondrial function, resulting in greater energy-producing capacity and decreased reactive oxygen species production.
Department of Pharmacology, University of California Irvine, CA 92697, USA.
Chris
C
Stirone
Sue P
SP
Duckles
Diana N
DN
Krause
Vincent
V
Procaccio
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344
D004791:Enzyme Inhibitors; D004958:Estradiol; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D002950:Citrate (si)-Synthase