Abstract 212: Estrogen Protects against Aneurysmal Rupture Through Estrogen Receptor-beta in Ovariectomized Mice

Abstract

Introduction Epidemiological studies suggest that estrogen has protective effects against the formation and rupture of intracranial aneurysms. Post-menopausal women are at a higher risk for aneurysmal rupture. In our mouse model of intracranial aneurysms, aneurysmal rupture occurs at a high incidence and results in neurological symptoms. We hypothesized that estrogen or stimulation of estrogen receptors (ERs) is protective against aneurysmal rupture in ovariectomized female mice. We also sought to determine the role of ER subtypes on aneurysmal rupture. Methods All female mice received bilateral ovariectomy. Intracranial aneurysms were induced using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started 2-week treatment with vehicle (n=19), 17β-estradiol (n=17) with (n=14) or without ER antagonist, ERα agonist (n=12), or ERβ agonist (n=15). Nitric oxide synthase (NOS) inhibitor (L-NAME, n=15) was used to determine roles of NOS in ER mediated prevention of aneurysmal rupture. Aneurysmal rupture was detected by neurological symptoms. Results 17β-estradiol (E2) reduced rupture rates in ovariectomized female mice (P < 0.05). ER antagonist reversed the protective effect of E2 on the aneurysmal rupture (P < 0.05). While ERα agonist did not prevent aneurysmal rupture, ERβ agonist reduced the rupture rate (P < 0.05). Inhibition of NOS by L-NAME abolished the protective effects of ERβ agonist on aneurysmal rupture (P < 0.05) (Figure). Conclusion These findings suggest that estrogen protects against aneurysmal rupture through ERβ activation. In addition, the protective effect of estrogen through ERβ is dependent on NOS. ERβ an NOS may be used as therapeutic targets for the prevention of aneurysmal rupture in post-menopausal women