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AGE AND ESTROGEN EFFECT ON MECHANISMS OF VASODILATION

年龄和雌激素对血管舒张机制的影响

基本信息

批准号：
2633368
负责人：
CATHY A DAVISON
金额：
$ 7.75万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 1999-02-28
项目状态：
已结题

项目摘要

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.

衰老与高血压和其他疾病的发病率增加有关心血管疾病。绝经前女性的发病率较低心血管疾病的发生率高于同龄男性或绝经后女性。自从绝经后妇女的雌激素替代疗法具有重要意义预防心血管疾病的发展，已被证实假设雌激素对心血管有益系统。该提案的重点是研究年龄的影响（从青年期到中年期）和长期体内雌激素作用于血管内皮的血管舒张连接处。实验旨在检验三个假设：1）对血管收缩剂会随着年龄的增长和对内皮细胞的反应而增加依赖性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舒张的内皮介质（一氧化氮，内皮衍生的超极化因子和环氧合酶产物）会随着年龄的增长而改变； 3）雌激素会增强激动剂诱导的幼鼠动脉内皮一氧化氮的产生增强内皮源性超极化因子的产生中年鼠。这些假设将通过研究内皮细胞来检验乙酰胆碱和选择性组胺 H/1 依赖性血管舒张年轻（13周）和中年肠系膜小动脉的激动剂（9-10个月）雌性大鼠。每个年龄的三组大鼠将被研究：卵巢完整、卵巢切除、卵巢切除加雌激素替代品。已知内皮依赖性的药理学抑制剂血管舒张途径（一氧化氮、花生四烯酸环氧合酶产物）酸代谢和内皮衍生的超极化因子）将用于确定每个途径对内皮细胞的贡献- 年轻和中年大鼠的依赖性血管舒张，并进一步确定雌激素对这些途径的影响。蛋白质印迹分析对于内皮一氧化氮合酶（eNOS）将用于确定 eNOS 蛋白的组织水平是否随年龄或雌激素治疗而变化。这些研究结果将提供重要的新信息关于雌激素对衰老背景的体内影响动脉和内皮功能。如果精确的机制雌激素对心血管系统具有有益作用待确定，也许可以设计出新的治疗剂专门针对影响其他系统的心血管系统雌激素反应组织。