Roles of Estrogen in the Formation of Intracranial Aneurysms in Ovariectomized Female Mice

BACKGROUND: Epidemiological studies have indicated that postmenopausal women have a higher incidence of intracranial aneurysms than men in the same age group. OBJECTIVE: To investigate whether estrogen or estrogen receptors (ERs) mediate protective effects against the formation of intracranial aneurysms. METHODS: Intracranial aneurysms were induced in mice by combining a single injection of elastase into the cerebrospinal fluid with deoxycorticosterone acetate salt hypertension. The mice were treated with estrogen (17 beta-estradiol), an ER alpha agonist (propyl pyrazole triol), and an ER beta agonist (diarylpropionitrile) with and without a nitric oxide synthase inhibitor. RESULTS: The ovariectomized female mice had a significantly higher incidence of aneurysms than the male mice, which was consistent with findings in previous epidemiological studies. In ovariectomized female mice, an ER beta agonist, but not an ER alpha agonist or 17 beta-estradiol, significantly reduced the incidence of aneurysms. The protective effect of the ER beta agonist was absent in the ovariectomized ER beta knockout mice. The protective effect of the ER beta agonist was negated by treatment with a nitric oxide synthase inhibitor. CONCLUSION: The effects of sex, menopause, and estrogen treatment observed in this animal study were consistent with previous epidemiological findings. Stimulation of estrogen receptor-beta was protective against the formation of intracranial aneurysms in ovariectomized female mice.