ESTROGEN STATUS AND THE FUNCTION OF CORONARY ARTERIES

流行病学和实验研究表明，雌激素治疗可减少女性和雌性实验动物的心血管疾病。雌激素直接影响内皮细胞和平滑肌细胞的功能。雌激素还可以通过调节血液元素的功能来影响心血管疾病的发生。雌激素对血小板的影响是鲜为人知的和有争议的。了解雌激素治疗如何调节血小板是很重要的，因为血小板是血管损伤部位的生理“第一反应者”，无论是机械性剥落还是内皮功能障碍。由于血小板释放血管活性因子和有丝分裂因子，它们是建立血管立即收缩和血管壁长期重塑条件的关键。这项更新应用的中心假设是，雌激素替代通过降低血小板活化、血小板衍生的血管活性因子和有丝分裂因子的释放以及内皮和血管平滑肌对血小板衍生因子的反应来降低血管对损伤的反应。雌激素的这些作用需要基因组和非基因组受体介导的机制。将采用一种独特的方法来研究雌激素对体外和体内血小板计数、易怒、含量和周转的影响。血小板功能与雌激素受体表达之间的关系将在雌激素治疗动物和缺乏雌激素受体的小鼠（雌激素受体敲除小鼠）中进行鉴定。内皮源性一氧化氮和内皮素- 1的产生将在雌激素处理动物的血小板源性因子的反应中进行检测。此外，细胞内钙、平滑肌的收缩和增殖对血小板因子的调节也将被检查。由于血栓形成是女性使用包括新型选择性雌激素受体调节剂（SERMS）在内的雌激素替代疗法的主要副作用，为了更好地了解雌激素对血小板功能的特异性影响以及血小板与血管壁的相互作用，需要进行系统的研究。本方案的实验采用了这样一种方法，利用分子来整合整个动物生理学。

Epidemiological and experimental studies indicate that estrogen treatment reduces cardiovascular disease in women and female experimental animals. Estrogen directly affects functions of endothelial and smooth muscle cells. Estrogen could also influence development of cardiovascular disease through modulating functions of blood elements. Effects of estrogen on platelets are little known and controversial. Understanding how estrogen therapy modulates platelets is important as platelets are physiological "first-responders" at the site of vascular injury be it mechanical denudation or endothelial dysfunction. Since platelets release both vasoactive and mitogenic factors, they are key in establishing conditions for immediate vasoconstriction and long-term remodeling of the vascular wall. The central hypothesis of this renewal application is that estrogen replacement REDUCES vascular response to injury by reducing platelet activation, release of platelet- derived vasoactive and mitogenic factors and responses of endothelium and vascular smooth muscle to platelet-derived factors. These actions of estrogen require both genomic and non-genomic receptor-mediated mechanisms. A unique approach will be taken to examine effects of estrogen on platelet count, irritability, contents and turnover in vitro and in vivo. Relationship between platelet functions and expression of estrogen receptors will be identified in estrogen-treated animals and mice lacking estrogen receptors (estrogen receptor knockout mice). Production of endothelium-derived nitric oxide and endothelin-l will be examined in response to platelet-derived factors from estrogen-treated animals. In addition, regulation of intracellular calcium, contraction and proliferation of the smooth muscle to platelet- factors will be examined. As thrombosis is a major side-effect in women taking estrogen replacement therapy including the new selective estrogen receptor modulators (SERMS), systematic studies are needed in order to better understand specific effects of estrogens on platelet function and interaction of platelets with the vascular wall. The experiments of this proposal take such an approach using molecular to integrated whole animal physiology.