Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Ave, No 3C-38, San Francisco, CA 94110.
Hypertension. 2014 Jun;63(6):1339-44. doi: 10.1161/HYPERTENSIONAHA.114.03300. Epub 2014 Apr 14.
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.
临床观察表明，绝经后女性的动脉瘤破裂发生率高于绝经前女性。我们假设雌激素相对缺乏可能会增加绝经后女性动脉瘤生长和蛛网膜下腔出血的风险。我们评估了雌激素和选择性雌激素受体亚型激动剂对去卵巢雌性小鼠颅内动脉瘤破裂发展的影响。我们使用了一种颅内动脉瘤小鼠模型，该模型再现了人类颅内动脉瘤的关键特征，包括自发性破裂。10 至 12 周龄的去卵巢雌性小鼠在动脉瘤诱导后 6 天开始接受雌激素、非选择性雌激素受体拮抗剂、雌激素受体-α激动剂或雌激素受体-β激动剂治疗，以使治疗影响动脉瘤破裂的发展而不影响动脉瘤的形成。雌激素显著降低了去卵巢小鼠破裂性动脉瘤的发生率和破裂率。非选择性雌激素受体拮抗剂消除了雌激素的保护作用。虽然雌激素受体-α激动剂对破裂性动脉瘤的发生率或破裂率没有影响，但雌激素受体-β激动剂可防止动脉瘤破裂，而不影响动脉瘤的形成。一氧化氮合酶的抑制消除了雌激素受体-β激动剂的保护作用。我们表明，雌激素可防止去卵巢雌性小鼠的动脉瘤破裂。雌激素的保护作用似乎是通过激活雌激素受体-β来实现的，雌激素受体-β是人类颅内动脉瘤和脑动脉中主要的雌激素受体亚型。
