Atherosclerosis Stage, Estrogen Receptors, and Vascular Responses to Estrogen

描述：绝经后雌激素替代疗法(E)是否对心血管有好处，在医学上争议最大的问题很少。很多猜测都与绝经后雌激素治疗时机对冠心病预后的影响有关。我们实验室的研究表明，动脉粥样硬化的阶段和/或绝经后开始治疗的时间是E有利影响动脉壁病理生理能力的关键决定因素。E在非人类灵长类动物动脉粥样硬化形成的早期(即冠状动脉有脂肪条纹或最初的脂肪斑块)具有最大的动脉粥样硬化抑制作用，而对于晚期动脉粥样硬化斑块，传统E几乎没有什么有益的作用。我们猴子研究的结果对Howard Hodis1博士决定计划和启动雌激素(ELITE)早期与晚期干预试验具有重要意义，该试验目前由美国国家老龄研究所(Grant#5R01AG024154)资助。拟议的研究是精英研究的配套研究，使我们能够进行女性无法进行的研究，这将补充和加强对精英数据的解释。对E的不同反应可能与绝经晚期(晚期病变)血管雌激素受体(ER)表达缺失有关，我们观察到绝经后猕猴动脉粥样硬化程度与ER表达呈负相关。我们认为，E的动脉粥样硬化保护作用将取决于治疗前动脉ER的表达水平，这可以在猴子身上测量，但在女性身上不能。此外，我们认为，与短期绝经期间产生的早期病变(脂肪条纹)相比，E对绝经多年形成的晚期病变(斑块)的影响将有很大不同。我们的方法将是利用组织学、免疫组织学、生化和定量分子方法来探索雌激素受体的表达和E(17升雌二醇)对动脉生物终点的不同作用机制，包括治疗前绝经后短期和长期(早期和晚期动脉粥样硬化)的手术后猴子的病变形态和基因表达。这些结果将增加我们对雌激素治疗对绝经早期和晚期动脉粥样硬化进展的影响的理解，对于经历潮热和其他更年期症状的女性来说，这是一个至关重要的公共卫生问题，她们面临着如何在不增加中风或心肌梗死等不良后果风险的情况下安全缓解这些问题的决定。

DESCRIPTION: Few, if any, issues in medicine have been more controversial than whether postmenopausal estrogen replacement (E) provides cardiovascular benefits. Much of the speculation concerns the impact of timing of postmenopausal estrogen treatment on coronary heart disease outcomes. Studies in our laboratories indicate that the stage of atherosclerosis and/or time while postmenopausal at initiation of treatment is a critical determinant of the ability of E to favorably affect arterial wall pathophysiology. E has its greatest atheroinhibitory effects in nonhuman primates early in atherosclerosis development (i.e., with coronary artery fatty streaks or initial fatty plaques), whereas with advanced atherosclerotic plaques, traditional E has few beneficial effects. Findings from our monkey studies were important in Dr. Howard Hodis1 decision to plan and initiate the Early versus Late Intervention Trial with Estradiol (ELITE), now funded by the National Institute of Aging (Grant #5R01AG024154). The proposed research is a companion study to ELITE, enabling us to conduct studies impossible to do in women, which will complement and enhance the interpretation of the ELITE data. Differential responses to E may relate to loss of vascular estrogen receptor (ER) expression in late menopause (advanced lesions), and we have observed an inverse relationship between atherosclerosis extent and ER expression in postmenopausal monkeys. We propose that atheroprotective effects of E will be dependent on the level of expression of arterial ER prior to treatment, which can be measured in monkeys but not in women. Furthermore, we propose E will have considerably different effects in advanced lesions (plaques) developed while menopausal for years compared to early lesions (fatty streaks) produced over a short menopausal period. Our approach will be to utilize histologic, immunohistologic, biochemical, and quantitative molecular methods to explore ER expression and mechanisms underlying differential effects of E (17li estradiol) on arterial biologic endpoints including lesion morphology and gene expression in surgically postmenopausal monkeys with short and long postmenopausal period before treatment (early vs. late stage atherosclerosis). The results will increase our understanding of the effects of estrogen treatment on the progression of atherosclerosis in early and late menopause, an issue of critical public health significance for women experiencing hot flushes and other menopausal symptoms faced with decisions on how to ease these problems safely without increasing the risk of adverse outcomes, such as stroke or myocardial infarction.