ESTROGEN STATUS AND THE FUNCTION OF CORONARY ARTERIES

流行病学和实验研究表明，雌激素治疗可以减少女性和雌性实验动物的心血管疾病。雌激素直接影响血管内皮细胞和平滑肌细胞的功能。雌激素还可通过调节血液元素的功能影响心血管疾病的发生发展。雌激素对血小板的影响鲜为人知，也存在争议。了解雌激素治疗如何调节血小板是很重要的，因为在血管损伤部位，无论是机械性剥脱还是内皮功能障碍，血小板都是生理性的“第一反应者”。由于血小板既能释放血管活性因子又能释放有丝分裂因子，因此它们是血管即刻收缩和血管壁长期重塑的关键因素。这一更新应用的中心假设是，雌激素替代通过减少血小板激活、血小板衍生的血管活性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减少血管损伤反应。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。将采取一种独特的方法来检测雌激素对体外和体内血小板计数、刺激性、含量和周转率的影响。在接受雌激素治疗的动物和缺乏雌激素受体的小鼠(雌激素受体基因敲除小鼠)中，将确定血小板功能和雌激素受体表达之间的关系。将检测内皮衍生一氧化氮和内皮素-L的产生，以响应来自雌激素处理的动物的血小板衍生因子。此外，还将研究细胞内钙离子、平滑肌收缩和增殖对血小板因子的调节作用。由于血栓形成是接受雌激素替代治疗的女性的主要副作用，包括新的选择性雌激素受体调节剂(SERMS)，因此需要进行系统研究，以更好地了解雌激素对血小板功能的特定影响以及血小板与血管壁的相互作用。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.