Intracranial aneurysm pathogenesis-roles of vascular remodeling and inflammation

描述(申请人提供)：我们将研究雌激素在颅内动脉瘤病理生理学中的作用。女性颅内动脉瘤和蛛网膜下腔出血的发生率高于男性。然而，女性在颅内动脉瘤和蛛网膜下腔出血的发病率上的优势只有在绝经年龄后才变得明显。此外，雌激素替代治疗降低了绝经后妇女动脉瘤性蛛网膜下腔出血的风险。我们使用一种新开发的小鼠颅内动脉瘤模型的初步数据显示，卵巢切除(手术绝经)增加了雌性小鼠的颅内动脉瘤发生率。而且，雌激素治疗降低了去卵巢小鼠的动脉瘤发生率。当卵巢摘除(延迟雌激素替代)后没有立即开始雌激素治疗时，外源性雌激素的保护作用显著降低，这与“时机假说”是一致的，即血管和炎性细胞对雌激素的反应在长时间的低雌激素作用后改变。我们的一般假设是雌激素对颅内动脉瘤的形成具有保护作用。此外，我们假设雌激素的保护作用是通过造血细胞(主要是炎性细胞)实现的。目的1确定雌激素受体-a(ERa)和雌激素受体？(ER？)在颅内动脉瘤形成中的作用。我们假设雌激素的保护作用主要是由雌激素受体-a(ERA)介导的。我们将利用ERA基因敲除小鼠、ER基因敲除小鼠和受体亚型特异性激动剂。目的2是确定介导雌激素对颅内动脉瘤形成的保护作用的细胞类型。我们假设雌激素对动脉瘤形成的保护作用主要是通过造血细胞(主要是炎性细胞)实现的。目的3是确定导致雌激素在长期低雌激素状态下保护作用减弱的细胞类型和受体亚型。我们推测，在长时间的低雌激素作用后，雌激素的保护作用的丧失是由于在长时间的低雌激素作用期间，造血细胞中缺乏雌激素对ERA的刺激。这些结果将为雌激素在颅内动脉瘤的病理生理学中的作用以及性别差异的机制提供新的见解。作为第一步，我们将重点研究雌激素在绝经后女性颅内动脉瘤形成中的作用。这项研究将为未来研究开发针对特定组织中特定雌激素受体亚型的新疗法奠定基础，以防止颅内动脉瘤的生长和破裂，特别是在绝经后有高风险患动脉瘤性蛛网膜下腔出血的女性。

DESCRIPTION (provided by applicant): We will study roles of estrogen in the pathophysiology of intracranial aneurysms. Incidence of intracranial aneurysms and subarachnoid hemorrhage are higher in women than in men. However, the female preponderance in incidence of intracranial aneurysms and subarachnoid hemorrhage becomes significant only after the menopausal age. Furthermore, estrogen replacement therapy reduces the risk for aneurysmal subarachnoid hemorrhage in post-menopausal women. Our preliminary data using a newly developed mouse model of intracranial aneurysm show that ovariectomy (surgical menopause) increased the incidence of intracranial aneurysms in female mice. And, estrogen treatment reduced the incidence of aneurysms in ovariectomized mice. The protective effects of exogenous estrogen were significantly reduced when the estrogen therapy did not start immediately after ovariectomy (delayed estrogen replacement), consistent with the "timing hypothesis," which states that responses of vascular and inflammatory cells to estrogen are altered after a long period of hypoestrogenicity. Our general hypothesis is that estrogen has protective effects against the formation of intracranial aneurysms. Furthermore, we hypothesize that the protective effects of estrogen are through hematopoietic cells (primarily inflammatory cells). Aim 1 is to determine contributions of estrogen receptor-a(ERa) and estrogen receptor-¿ (ER¿) to the formation of intracranial aneurysms. We hypothesize that the protective effects of estrogen are primarily mediated by estrogen receptor-a (ERa). We will utilize ERa knockout mice, ER¿ knockout mice, and receptor subtype specific agonists. Aim 2 is to determine the cell type that is mediating estrogen's protective effects against the formation of intracranial aneurysms. We hypothesize that the protective effects of estrogen against aneurysm formation are primarily through hematopoietic cells (primarily inflammatory cells). Aim 3 is to identify the cell type and receptor subtype responsible for the reduced protective effects of estrogen after a prolonged period of hypoestrogenicity. We hypothesize that the loss of protective effects of estrogen after a prolonged period of hypoestrogenicity is due to the lack of estrogen stimulation on ERa in hematopoietic cells during the prolonged hypoestrogenic period. Results will provide new insights into the roles of estrogen in the pathophysiology of intracranial aneurysms and mechanisms for the gender difference. As a first step, we will focus on roles of estrogen in the formation of intracranial aneurysms in post-menopausal women. This study will be a basis for future studies to develop new therapies that target specific estrogen receptor subtype in specific tissues for the prevention of growth and rupture of intracranial aneurysms, especially in post-menopausal women who are at high risk for aneurysmal subarachnoid hemorrhage.