ESTROGEN/PLATELET INTERACTION IN CEREBRAL ISCHEMIA

脑血管系统中的血小板活化被认为是中风或其他缺血性事件后组织损伤的介体。 数据表明，绝经前女性患心血管疾病（包括中风和短暂性脑缺血发作）的风险低于男性，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，但围绕雌激素治疗的风险与益处的争议。 最近的研究表明，增加雌激素水平促进抗聚集血管扩张剂一氧化氮（NO）的表达，同时抑制血小板粘附分子P-选择素的表达。 我们建议研究升高的雌激素对血小板生物学的影响，以确定激素是否通过表达血管收缩性血小板产物来调节缺血前后血小板功能或微血管血管舒张能力的改变。 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弱粘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舒张能力的变化。 目的3研究NO与P-选择素表达的相互关系。 我们将确定，如果在两个生理剂量的慢性雌激素治疗的影响，通过抑制缺血后血小板和内皮细胞P-选择素作为一氧化氮产生增加的结果，改善微血管灌注。 我们将使用全血血小板聚集，活体显微镜，免疫学和生物化学技术，以确定如何雌激素影响血小板生物学和微血管内皮功能。 本研究将阐明外源性雌激素治疗在缺血性脑损伤中的作用机制和剂量。 这些都是重要的考虑因素，影响护理治疗的争议，雌激素替代疗法的安全性和有效性。

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.