title: Estrogen protects against intracranial aneurysm rupture in ovariectomized mice.
abstract: Clinical observations suggest that postmenopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks of aneurysmal growth and subarachnoid hemorrhage in postmenopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. We used an intracranial aneurysm mouse model that recapitulates the key features of human intracranial aneurysms, including spontaneous rupture. Ten- to 12-week-old ovariectomized female mice received treatment with estrogen, nonselective estrogen receptor antagonist, estrogen receptor-α agonist, or estrogen receptor-β agonist starting 6 days after aneurysm induction so that the treatments affected the development of aneurysmal rupture without affecting aneurysmal formation. Estrogen significantly reduced the incidence of ruptured aneurysms and rupture rates in ovariectomized mice. Nonselective estrogen receptor antagonist abolished the protective effect of estrogen. Although estrogen receptor-α agonist did not affect the incidence of ruptured aneurysms or rupture rates, estrogen receptor-β agonist prevented aneurysmal rupture without affecting the formation of aneurysms. The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen seemed to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, No 3C-38, San Francisco, CA 94110. hashimot@anesthesia.ucsf.edu.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Tada
authors.forename: Kosuke
authors.initials: K
authors.lastname: Wada
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Makino
authors.forename: Elena I
authors.initials: EI
authors.lastname: Liang
authors.forename: Shoko
authors.initials: S
authors.lastname: Murakami
authors.forename: Mari
authors.initials: M
authors.lastname: Kudo
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Shikata
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Pena Silva
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.forename: David M
authors.initials: DM
authors.lastname: Hasan
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kanematsu
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
authors.forename: Tomoki
authors.initials: T
authors.lastname: Hashimoto
mesh_terms: D000368:Aged; D017542:Aneurysm, Ruptured / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D002532:Intracranial Aneurysm / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010052:Ovariectomy; D010636:Phenols; D011720:Pyrazoles / Q000494:pharmacology; D013345:Subarachnoid Hemorrhage / Q000378:metabolism / Q000517:prevention & control; D011422:Propionates
chemical_list: D004791:Enzyme Inhibitors; D004958:Estradiol; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D000077267:Fulvestrant; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol
keywords: estrogens; menopause; models, animal
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