ESTROGEN/PLATELET INTERACTION IN CEREBRAL ISCHEMIA

脑血管系统中的血小板激活被认为是中风或其他缺血事件后组织损伤的中介。数据表明，绝经前女性患包括中风和短暂性脑缺血发作在内的心血管疾病的风险比男性低，这可能是由于雌激素对血小板生物学或血管功能的影响。许多女性选择接受激素替代疗法，但围绕雌激素疗法的风险和好处存在争议。最近的研究表明，雌激素水平的增加促进了抗聚集血管扩张剂一氧化氮(NO)的表达，同时抑制了血小板黏附分子P-选择素的形成。我们建议研究雌激素升高对血小板生物学的影响，以确定激素是否通过血管收缩血小板产物的表达来缓和缺血前后血小板功能或微血管扩张能力的变化。在目标1中，我们将确定两种生理剂量的慢性雌激素是否通过P-选择素介导的机制在基线或全脑缺血后调节血小板生物学。在目标2中，我们将测试两种生理剂量的慢性雌激素是否通过减少黏附或血管活性血小板产物的释放来调节缺血后软脑膜血管扩张能力的变化。目的3研究NO与P-选择素表达的相互关系。我们将确定，两种生理剂量的慢性雌激素治疗是否通过抑制缺血后血小板和内皮P-选择素而改善微血管灌注量，这是由于一氧化氮产生增加的结果。我们将使用全血血小板聚集测定、活体显微镜、免疫学和生化技术来确定雌激素如何影响血小板生物学和微血管内皮功能。本项目中提出的研究将从机制和剂量两个方面阐明外源性雌激素治疗在缺血性脑损伤中的作用。考虑到围绕雌激素替代疗法的安全性和有效性的争议，这些都是影响护理治疗的重要因素。

Platelet activation in the cerebrovasculature has been implicated as a mediator of tissue injury following stroke or other ischemic events. Data suggest that pre-menopausal women are at lower risk than men for cardiovascular diseases including stroke and transient ischemic attacks, conceivably due to the effects of estrogenic hormones on platelet biology or vascular function. Many women make a choice to receive hormone replacement therapy, but controversy surrounds the risks versus the benefits of estrogen therapy. Recent studies indicate that increasing estrogen levels promotes expression of the antiaggregant vasodilator, nitric oxide (NO), while depressing platelet elaboration of the adhesion molecule, P-selectin. We propose to study the effects of elevated estrogen on platelet biology to determine if the hormone moderates alterations in pre and post-ischemic platelet function or microvascular vasodilator capacity via the expression of vasoconstrictive platelet products. In Aim 1 we will determine if chronic estrogen in two physiologic doses modulates platelet biologic via a P-selectin mediated mechanism at baseline or after global cerebral ischemia. In Aim 2 we will test if chronic estrogen in two physiologic doses modulates changes in post-ischemia pial vessel vasodilatory capacity via attenuation of the release of adhesive or vasoactive platelet products. In Aim 3 we study the interrelationship between NO and P-selectin expression. We will determine, if the effects of chronic estrogen treatment in two physiologic doses improves microvascular perfusion by depressing post-ischemic platelet and endothelial P-selectin as a result of increased nitric oxide production. We will use whole blood platelet aggregometry, intravital microscopy, immunological and biochemical techniques to ascertain how estrogen affects platelet biology and microvascular endothelial function. The studies proposed in this project will clarify the contribution of exogenous estrogen therapy in ischemic brain injury both mechanistically and according to dosage. These are important considerations which impact nursing therapeutics given the controversy surrounding the safety and efficacy of estrogen replacement regimens.