AGE AND ESTROGEN EFFECT ON MECHANISMS OF VASODILATION

老龄化与高血压和其他疾病的发病率增加有关 心血管疾病。绝经前的妇女有较低的 心血管疾病的发病率高于年龄匹配的男性或绝经后女性。自.以来 绝经后妇女的雌激素替代疗法提供了显著的 防止心血管疾病的发展，它已经被 假设雌激素对心血管有有益作用 系统。这项建议的重点是研究年龄的影响。 (从青壮年到中年)和体内的长期 雌激素对血管内皮细胞血管扩张剂连接的影响。 实验旨在检验三个假设：1)对 血管收缩物质会随着年龄和对内皮的反应性而增加- 依赖的血管扩张剂会随着年龄的增长而减少；2)相对重要性 各种血管扩张的内皮介质(一氧化氮， 内皮源性超极化因子和环氧合酶产物) 将随年龄变化；以及3)雌激素将增强激动剂诱导的 幼年大鼠动脉内皮细胞一氧化氮的产生 促进血管内皮源性超极化因子的产生 中年大鼠。这些假说将通过研究内皮细胞来检验。 对乙酰胆碱和选择性组胺H/1的依赖性血管扩张 青年(13周)和中年肠系膜小动脉的激动剂 (9-10月龄)雌性大鼠。每个年龄段的三组大鼠 研究：卵巢完整，卵巢切除，卵巢切除加雌激素 替补。已知的内皮依赖性药物抑制物 血管扩张途径(一氧化氮、花生四烯酸环氧合酶产物 酸代谢和内皮衍生超极化因子)将是 用来确定每条通路对内皮的贡献- 青年和中年大鼠的依赖性血管扩张，并进一步 确定雌激素对这些途径的影响。Westernblot分析 对于内皮，将使用一氧化氮合酶(ENOS)来确定 组织eNOS蛋白水平是否随年龄或雌激素治疗而变化。 这些研究的结果将提供重要的新信息。 关于雌激素在衰老背景下的体内效应 动脉和内皮功能。如果它所依据的精确机制 雌激素对心血管系统的有益作用可以 下定决心，也许可以设计出新的治疗剂 特别针对影响其他人的心血管系统 雌激素反应组织。

Aging is associated with an increased incidence of hypertension and other cardiovascular diseases. Premenopausal women have a lower rate of cardiovascular disease than age-matched men or postmenopausal women. Since estrogen replacement therapy in postmenopausal women provides significant protection against the development of cardiovascular disease, it has been hypothesized that estrogen has beneficial effects on the cardiovascular system. The focus of this proposal is the study of the effects of age (progressing from young adulthood to middle age) and long-term in vivo estrogen on the vasodilator junctions of the vascular endothelium. Experiments are designed to test three hypotheses: 1) responsiveness to vasoconstrictors will increase with age and responsiveness to endothelium- dependent vasodilators will decrease with age; 2) the relative importance of various endothelial mediators of vasodilation (nitric oxide, endothelium-derived hyperpolarizing factors, and cyclooxygenase products) will change with age; and 3) estrogen will enhance agonist-induced endothelial nitric oxide production in arteries from young rats and enhance the production of endothelium-derived hyperpolarizing factors in middle age rats. These hypotheses will be tested by studying endothelium- dependent vasodilations to acetylcholine and a selective histamine H/1 agonist in small mesenteric arteries from young (13 weeks) and middle age (9-10 months) female rats. Three groups of rats of each age will be studied: ovary-intact, ovariectomized, and ovariectomized plus estrogen replacement. Pharmacological inhibitors of known endothelium-dependent vasodilator pathways (nitric oxide, cyclooxygenase products of arachidonic acid metabolism, and endothelium-derived hyperpolarizing factors) will be employed to determined the contribution of each pathway to endothelium- dependent vasodilation in young and middle age rats, and to further determine the effects of estrogen on these pathways. Western blot analysis for endothelial nitric oxide synthase (eNOS) will be used to determine whether tissue levels of eNOS protein change with age or estrogen therapy. The results of these studies will provide important new information regarding the in vivo effects of estrogen on a background of aging arterial and endothelial function. If the precise mechanisms by which estrogen affords its beneficial effects on the cardiovascular system can be determined, perhaps new therapeutic agents can be designed that will specifically target the cardiovascular system that effects on other estrogen-responsive tissues.