Abstract
BackgroundEstrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats.MethodsTen-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed.ResultsDuring 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERβ, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1β and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERβ and decreased the level of interleukin-1β and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERβ.ConclusionsOur observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.
Highlights
Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women
BZA prevents aneurysmal rupture in rats To determine whether estrogen deficiency increases while BZA decreases the incidence of cerebral aneurysm rupture in estrogen-deficient rats, we compared the incidence of rupture during 12 weeks of observation in hypertensive ovariectomized aneurysm rats treated with vehicle (HT +OVX), 0.3 mg/kg BZA (BZA0.3), or 1 mg/kg BZA (BZA1) and in hypertensive sham-ovariectomized rats (HT rats)
These results suggest that estrogen deficiency promoted aneurysm rupture in the presence of hypertension, while BZA inhibited its effect in a blood pressure-independent manner
Summary
Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. The incidence of cerebral aneurysms and SAH is higher in post- than premenopausal women [2, 3]. Estrogen (17β-estradiol) and an estrogen receptor β (ERβ)-, but not an ERα agonist, reduced the incidence of cerebral aneurysm rupture in ovariectomized mice [9]. These findings suggest that ERrelated drugs may help to prevent SAH. Postmenopausal estrogen replacement therapy reduced the risk of SAH [10,11,12] but increased the risk for breast and endometrial cancer, stroke, and venous thromboembolism [9, 13,14,15]
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