Atherosclerosis Stage, Estrogen Receptors, and Vascular Responses to Estrogen

描述：在医学上，很少有问题比绝经后雌激素替代(E)是否对心血管有益更有争议。许多推测都与绝经后雌激素治疗时间对冠心病结局的影响有关。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对动脉壁病理生理有利影响能力的关键决定因素。E在动脉粥样硬化发展早期（即冠状动脉脂肪条纹或初始脂肪斑块）的非人灵长类动物中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几乎没有有益作用。我们的猴子研究结果对Howard Hodis1博士决定计划和启动雌二醇早期与晚期干预试验（ELITE）非常重要，该试验现在由国家衰老研究所资助（授权号5R01AG024154）。拟议的研究是ELITE的伴随研究，使我们能够进行不可能在女性中进行的研究，这将补充和加强对ELITE数据的解释。对E的不同反应可能与绝经后期（晚期病变）血管雌激素受体（ER）表达的丧失有关，我们已经观察到绝经后猴子动脉粥样硬化程度与ER表达呈反比关系。我们提出，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，这可以在猴子中测量，但不能在女性中测量。此外，我们认为E对绝经后多年形成的晚期病变（斑块）的影响与绝经后短时间内产生的早期病变（脂肪条纹）的影响大不相同。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表达和E （17li雌二醇）对动脉生物学终点的差异影响机制，包括治疗前短和长绝经后期（早期和晚期动脉粥样硬化）手术后猴子的病变形态和基因表达。该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妇女来说，这是一个具有重要公共卫生意义的问题，她们面临着如何在不增加不良后果（如中风或心肌梗死）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.