We will study roles of estrogen in the pathophysiology of intracranial aneurysms. Incidence of intracranial aneurysms and subarachnoid hemorrhage are higher in women than in men. However, the female preponderance in incidence of intracranial aneurysms and subarachnoid hemorrhage becomes significant only after the menopausal age. Furthermore, estrogen replacement therapy reduces the risk for aneurysmal subarachnoid hemorrhage in post-menopausal women. Our preliminary data using a newly developed mouse model of intracranial aneurysm show that ovariectomy (surgical menopause) increased the incidence of intracranial aneurysms in female mice. And, estrogen treatment reduced the incidence of aneurysms in ovariectomized mice. The protective effects of exogenous estrogen were significantly reduced when the estrogen therapy did not start immediately after ovariectomy (delayed estrogen replacement), consistent with the """"""""timing hypothesis,"""""""" which states that responses of vascular and inflammatory cells to estrogen are altered after a long period of hypoestrogenicity. Our general hypothesis is that estrogen has protective effects against the formation of intracranial aneurysms. Furthermore, we hypothesize that the protective effects of estrogen are through hematopoietic cells (primarily inflammatory cells).
Aim 1 is to determine contributions of estrogen receptor-a(ERa) and estrogen receptor-? (ER?) to the formation of intracranial aneurysms. We hypothesize that the protective effects of estrogen are primarily mediated by estrogen receptor-a (ERa). We will utilize ERa knockout mice, ER? knockout mice, and receptor subtype specific agonists.
Aim 2 is to determine the cell type that is mediating estrogen's protective effects against the formation of intracranial aneurysms. We hypothesize that the protective effects of estrogen against aneurysm formation are primarily through hematopoietic cells (primarily inflammatory cells).
Aim 3 is to identify the cell type and receptor subtype responsible for the reduced protective effects of estrogen after a prolonged period of hypoestrogenicity. We hypothesize that the loss of protective effects of estrogen after a prolonged period of hypoestrogenicity is due to the lack of estrogen stimulation on ERa in hematopoietic cells during the prolonged hypoestrogenic period. Results will provide new insights into the roles of estrogen in the pathophysiology of intracranial aneurysms and mechanisms for the gender difference. As a first step, we will focus on roles of estrogen in the formation of intracranial aneurysms in post-menopausal women. This study will be a basis for future studies to develop new therapies that target specific estrogen receptor subtype in specific tissues for the prevention of growth and rupture of intracranial aneurysms, especially in post-menopausal women who are at high risk for aneurysmal subarachnoid hemorrhage.

Public Health Relevance

This project will study roles of estrogen in the pathophysiology of intracranial aneurysms. This study will be a basis for future studies to develop a new therapy to target specific estrogen receptor subtype in specific tissues for the prevention of growth and rupture of intracranial aneurysms, especially in post-menopausal women who are at high risk for aneurysmal subarachnoid hemorrhage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS055876-05
Application #
8109088
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jacobs, Tom P
Project Start
2006-07-01
Project End
2016-02-29
Budget Start
2011-03-15
Budget End
2012-02-29
Support Year
5
Fiscal Year
2011
Total Cost
$337,969
Indirect Cost
Name
University of California San Francisco
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kamio, Yoshinobu; Miyamoto, Takeshi; Kimura, Tetsuro et al. (2018) Roles of Nicotine in the Development of Intracranial Aneurysm Rupture. Stroke 49:2445-2452
Kotoda, Masakazu; Furukawa, Hajime; Miyamoto, Takeshi et al. (2018) Role of Myeloid Lineage Cell Autophagy in Ischemic Brain Injury. Stroke 49:1488-1495
Cooke, Daniel L; McCoy, David B; Halbach, Van V et al. (2018) Endovascular Biopsy: In Vivo Cerebral Aneurysm Endothelial Cell Sampling and Gene Expression Analysis. Transl Stroke Res 9:20-33
Kawai, Tatsuo; Takayanagi, Takehiko; Forrester, Steven J et al. (2017) Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/?-Aminopropionitrile-Induced Abdominal Aortic Aneurysm. Hypertension 70:959-963
Hashimoto, Tomoki; Rizzo, Victor (2017) HIF1? in aortic aneurysms and beyond. Clin Sci (Lond) 131:621-623
Korai, Masaaki; Kitazato, Keiko T; Tada, Yoshiteru et al. (2016) Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats. J Neuroinflammation 13:165
Liu, Jia; Kuwabara, Atsushi; Kamio, Yoshinobu et al. (2016) Human Mesenchymal Stem Cell-Derived Microvesicles Prevent the Rupture of Intracranial Aneurysm in Part by Suppression of Mast Cell Activation via a PGE2-Dependent Mechanism. Stem Cells 34:2943-2955
Makino, Hiroshi; Hokamura, Kazuya; Natsume, Takahiro et al. (2015) Successful serial imaging of the mouse cerebral arteries using conventional 3-T magnetic resonance imaging. J Cereb Blood Flow Metab 35:1523-7
Shimada, Kenji; Furukawa, Hajime; Wada, Kosuke et al. (2015) Protective Role of Peroxisome Proliferator-Activated Receptor-? in the Development of Intracranial Aneurysm Rupture. Stroke 46:1664-72
Shimada, Kenji; Furukawa, Hajime; Wada, Kosuke et al. (2015) Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice. J Cereb Blood Flow Metab 35:1163-8

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