Women have lower stroke risk and mortality compared to age-matched men. While some of this protection appears to be mediated via ovarian estrogen, ovarian hormones do not account for all of the protective effects seen in females since female protection persists even after menopause when ovarian estrogen is lost. In post- menopausal women, the major source of estrogen becomes local (extra-gonadal) synthesis of estradiol by the enzyme aromatase. Aromatase is expressed in numerous cell types, including vascular endothelial cells (EC). In female mice, both aromatase gene deletion and pharmacological inhibition lead to worse outcome following cerebral ischemia, suggesting that aromatase plays a protective role. Therefore, the hypothesis to be tested is that females are protected from cerebrovascular dysfunction following cerebral ischemia compared to males due to higher expression and activity of endothelial-specific aromatase. In order to determine if there are sex differences in cerebrovascular endothelial dysfunction following cerebral ischemia in mice, responses to the endothelium-dependent vasodilator acetylcholine (ACh) will be compared in male and female mice before and after transient middle cerebral artery occlusion (tMCAO, 1h) or sham surgery using an in vivo cranial window preparation and optical microangiography imaging. To determine if sex differences in endothelium-dependent dilation after tMCAO are mediated by aromatase, ACh responses before and after tMCAO or sham surgery will be compared between wild-type and aromatase knockout mice of both sexes. Finally, to determine if there are sex differences in EC-specific aromatase expression and cerebrovascular aromatase activity, EC-specific aromatase mRNA and protein expression and cerebrovascular aromatase activity will be compared in cerebral vessels isolated from male and female mice at baseline or after tMCAO or sham surgery. Understanding EC specific regulation of aromatase may lead to therapeutic strategies aimed at enhancing local estradiol production specifically within endothelial cells, thus avoiding the negative side effects associated with global estrogen administration, but maintaining the protective effects of estrogen on the vasculature.

Public Health Relevance

Aromatase inhibitors, which are in use clinically for the treatment of hormone positive breast cancer, have been linked to adverse cardiovascular effects. The proposed research will use a rodent model of stroke, the middle cerebral artery occlusion, to determine the protective effect of aromatase (the enzyme that produces estradiol) against endothelial dysfunction following cerebral ischemia, especially in females. Understanding endothelial cell specific regulation of aromatase may lead to therapeutic strategies for stroke aimed at enhancing local estradiol production specifically within endothelial cells, thus avoiding the negative side effects associated with global estrogen administration, but maintaining the protective effects of estrogen on the vasculature.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS082017-02
Application #
8638785
Study Section
Special Emphasis Panel (ZRG1-F01-F (20))
Program Officer
Koenig, James I
Project Start
2012-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$52,190
Indirect Cost
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Zuloaga, Kristen L; Davis, Catherine M; Zhang, Wenri et al. (2014) Role of aromatase in sex-specific cerebrovascular endothelial function in mice. Am J Physiol Heart Circ Physiol 306:H929-37
Zuloaga, Kristen L; Krasnow, Stephanie M; Zhu, Xinxia et al. (2014) Mechanism of protection by soluble epoxide hydrolase inhibition in type 2 diabetic stroke. PLoS One 9:e97529
Jouihan, Sari A; Zuloaga, Kristen L; Zhang, Wenri et al. (2013) Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus. J Cereb Blood Flow Metab 33:1650-6