title: Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms.
abstract: Mitochondria support the energy-intensive functions of brain endothelium but also produce damaging-free radicals that lead to disease. Previously, we found that estrogen treatment protects cerebrovascular mitochondria, increasing capacity for ATP production while decreasing reactive oxygen species (ROS). To determine whether these effects occur specifically in endothelium in vivo and also explore underlying transcriptional mechanisms, we studied freshly isolated brain endothelial preparations from intact and ovariectomized female mice. This preparation reflects physiologic influences of circulating hormones, hemodynamic forces, and cell-cell interactions of the neurovascular unit. Loss of ovarian hormones affected endothelial expression of the key mitochondrial regulator family, peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), but in a unique way. Ovariectomy increased endothelial PGC-1α mRNA but decreased PGC-1β mRNA. The change in PGC-1β correlated with decreased mRNA for crucial downstream mitochondrial regulators, nuclear respiratory factor 1 and mitochondrial transcription factor A, as well as for ATP synthase and ROS protection enzymes, glutamate-cysteine ligase and manganese superoxide dismutase. Ovariectomy also decreased mitochondrial biogenesis (mitochondrial/nuclear DNA ratio). These results indicate ovarian hormones normally act through a distinctive regulatory pathway involving PGC-1β to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS protection.
authors.affiliation: Department of Pharmacology, University of California, Irvine, CA, USA.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Kemper
authors.forename: Yuanzi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Sue P
authors.initials: SP
authors.lastname: Duckles
authors.forename: Diana N
authors.initials: DN
authors.lastname: Krause
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000098:blood supply* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D010053:Ovary / Q000502:physiology* / Q000601:surgery; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D004272:DNA, Mitochondrial; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D025261:Mitochondrial Proton-Translocating ATPases