Mitochondrial dysfunction has been implicated as a cause of age-related disorders; however little is known regarding the role of mitochondria in vascular disease. We recently found that estrogen (E) has beneficial effects on cerebrovascular mitochondria that likely contribute to vasoprotection. Thus, our overall hypothesis is: Effects of E on mitochondrial function protect against cerebrovascular endothelial dysfunction with age. In this proposal, mechanisms and consequences of E modulation of cerebrovascular mitochondria will be determined both in vitro and in vivo. Cultured human brain endothelial cells will be used in the first two aims. HYPOTHESIS 1: E increases the efficiency of oxidative phosphorylation and decreases oxidative stress in cerebral endothelial mitochondria. Key indices of mitochondrial function, mitochondrial enzyme levels and activities, mitochondrial biogenesis, and production of reactive oxygen species (ROS) will be measured after E treatment in normal conditions and in culture models of ischemia. The involvement of E receptors (ERalpha and ERbeta) will be tested using selective siRNA knockdown, antagonists, agonists and selective ER modulators (SERMs). HYPOTHESIS 2: E regulates mitochondrial function via PGC-1 transcriptional coactivators. We will determine effects of E, and the role of ERs, on levels of mitochondria-related transcription factors, including the PGC-1 family. Specific involvement of PGC-1fi in mitochondrial effects of E will be tested using siRNA downregulation of PGC-1fi. ER-PGC-1fi interactions will be tested by immunoprecipitation.
In aim 3, a transgenic mouse model (MnSOD+/-) will be used to test HYPOTHESIS 3: In vivo E protects cerebrovascular mitochondria and decreases endothelial dysfunction with advancing age. Cerebral blood vessels will be isolated from intact, ovariectomized, and E-treated females of different ages to compare mitochondrial enzymes, ATP and ROS production, and damage to mitochondrial iron/sulphur- containing enzymes and mtDNA. Endothelial function will be assessed in pressurized segments of isolated middle cerebral arteries. This project will delineate novel ways in which estrogen and estrogen-related therapies modulate the cerebral vascular system. These studies may provide insight into the role of mitochondria in cerebrovascular dysfunction, a contributor to age-related disorders such as stroke and vascular dementia.
|Kemper, Martin F; Stirone, Chris; Krause, Diana N et al. (2014) Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection. Eur J Pharmacol 723:322-9|
|Kemper, Martin F; Zhao, Yuanzi; Duckles, Sue P et al. (2013) Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms. J Cereb Blood Flow Metab 33:122-8|
|Guo, Jiabin; Duckles, Sue P; Weiss, John H et al. (2012) 17?-Estradiol prevents cell death and mitochondrial dysfunction by an estrogen receptor-dependent mechanism in astrocytes after oxygen-glucose deprivation/reperfusion. Free Radic Biol Med 52:2151-60|
|Krause, D N; Duckles, S P; Gonzales, R J (2011) Local oestrogenic/androgenic balance in the cerebral vasculature. Acta Physiol (Oxf) 203:181-6|
|Duckles, S P; Krause, D N (2011) Mechanisms of cerebrovascular protection: oestrogen, inflammation and mitochondria. Acta Physiol (Oxf) 203:149-54|
|Duckles, Sue P; Miller, Virginia M (2010) Hormonal modulation of endothelial NO production. Pflugers Arch 459:841-51|
|Guo, Jiabin; Krause, Diana N; Horne, James et al. (2010) Estrogen-receptor-mediated protection of cerebral endothelial cell viability and mitochondrial function after ischemic insult in vitro. J Cereb Blood Flow Metab 30:545-54|
|Gonzales, Rayna J; Duckles, Sue P; Krause, Diana N (2009) Dihydrotestosterone stimulates cerebrovascular inflammation through NFkappaB, modulating contractile function. J Cereb Blood Flow Metab 29:244-53|
|Razmara, Ali; Sunday, Lorraine; Stirone, Chris et al. (2008) Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells. J Pharmacol Exp Ther 325:782-90|
|Miller, Virginia M; Duckles, Sue P (2008) Vascular actions of estrogens: functional implications. Pharmacol Rev 60:210-41|
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