application) Actions of estrogen on function of endothelial NOS may account for cerebrovascular protection. Thus, the first hypothesis is: 1) cerebrovascular responses involving NOS are affected by estrogen. Rat middle cerebral arteries in vitro will be used to test the influence of sex and gonadal steroids, comparing males and cycling females, control or gonadectomized and steroid-replaced. The investigator will compare myogenic tone in arteries from males and females and test whether NOS inhibition abolishes gender or estrous cycle differences. Possible K+ channel involvement will be investigated. Since shear stress stimulates the activity of NOS, the PI will test whether flow induced vasodilation is influenced by estrogen status and investigate modulation by gender and gonadal steroids. As a control, effects of gender and gonadal steroids on vasodilator responses to increased extracellular K+, which does not involve NOS will be investigated. The second hypothesis is: 2) estrogen acts by regulating levels of eNOS protein. Responses to endothelial dependent vasodilators, levels of NOS protein by Western blot and NOS activity will be measured, and NOSIII-deficient mice will be studied. For the third specific aim, the PI will test whether: 3) estrogen modulates effects of melatonin by a selective action on MT2 receptor mediated vasodilation. Circadian variation in cardiovascular disease onset has been shown and estrogen regulates vascular sensitivity to melatonin. The PI will determine whether melatonin causes constriction of cerebral arteries through MT1 and dilation via MT2 receptors. Influence of sex, transmural pressure, artery size and endothelial factors will be investigated. The PI will also test whether dilator responses via MT2 receptors are preferentially enhanced by estrogen exposure and using RT-PCR whether gonadal hormones alter expression of melatonin receptor subtypes. The final hypothesis is: 4) effects of estrogen are mediated by the classical estrogen receptor Estrogen receptor antagonists and estrogen receptor knockout mice will be used to test whether this receptor accounts for effects on cerebrovascular reactivity. Given the enormous impact of hormone replacement therapy, knowledge of the effects of gonadal steroids and melatonin on the cerebral circulation is essential.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL050775-06S1
Application #
6195076
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1994-07-01
Project End
2002-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
6
Fiscal Year
2000
Total Cost
$30,415
Indirect Cost
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
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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