ROLE OF NO AND ESTRADIOL IN AGING AND ATHEROGENESIS

在女性的衰老过程中，会发生两个影响血管系统的重要变化。第一种是绝经，与雌激素停用有关，另一种是内皮功能障碍，表现为内皮依赖性血管扩张功能下降，可能反映了内皮细胞产生NO的减少。这两个变化可以是相互独立的，也可以是相互关联的。我们和其他人已经证明，雌二醇(E2)增加了NO的产生。因此，在衰老和绝经期间出现的内皮功能障碍，表现为内皮依赖性血管扩张功能下降和NO产生减少，可能仅基于E2的减少。绝经后妇女的雌激素替代已被用于与心血管系统相关的潜在益处。然而，雌激素对心血管系统产生有益影响的确切机制(S)尚不清楚。另一方面，最近的一项研究表明，与安慰剂组相比，在研究的第一年，对患有有据可查的冠状动脉疾病的女性联合使用雌激素和孕激素与增加第二次冠状动脉事件的发生率有关。在这项研究中，没有一组女性只接受E2治疗。因此，一旦疾病确定，E2在调节动脉粥样硬化形成中的作用尚不清楚。同样，绝经后的女性偶尔会被注射睾丸素(T)来提高她们的性功能，但T对动脉粥样硬化形成的影响尚不清楚。有待检验的总体假设是，仅仅是E2或T的退出就会导致NO合成减少，从而导致血管壁的促炎反应，导致动脉粥样硬化早期出现的变化。一个推论可能是，极端的动脉粥样硬化过程可能会增加Oono的产生，在这种情况下，抑制可能实际上是有益的。我们建议通过卵巢摘除(OVX)来模拟实验动物的绝经后状态。我们建议通过给动物注射一种NO合成的抑制剂来通过药理学手段来模拟内皮功能障碍。这一假设将在三个具体目标下进行检验。

During aging in women, two important changes occur which affect the vascular system. The first is menopause which is associated with estrogen withdrawal and the other is endothelial dysfunction manifested by a decrease in endothelium dependent vasodilation, possibly a reflection of a decrease in NO production by endothelial cells. These two changes may be independent of each other or may be interlinked. We and others have demonstrated that estradiol (E2) increases NO production. Therefore, endothelial dysfunction seen during aging and menopause as manifested by a decrease in endothelium dependent vasodilation and decrease in NO production may be explained just on the basis of E2 withdrawal alone. Estrogen replacement to postmenopausal women has been utilized for potential benefits related to the cardiovascular system. However, the precise mechanism(s) by which estrogens exert a beneficial effect on the cardiovascular system is not known. On the other hand, a recent study indicates that administration of a combination of estrogen and a progestin to women with well-documented coronary artery disease was associated with an increase in the incidence of a second coronary event in the first year of the study compared to the placebo group. In this study, there was no group in which women received E2 alone. Therefore, the role of E2 in modulating atherogenesis, once the disease is established is not known. Similarly, post-menopausal women are occasionally administered testosterone (t) to increase their sexual function but the effect of T on atherogenesis is not known. The overall hypothesis to be tested is that "the mere withdrawal of E2 or T leads to a decrease in NO synthesis, and thereby, to a pro-inflammatory response of the vascular wall leading to changes seen early in atherogenesis. A corollary could be that the atherogenic process on the extreme might increase the production of OONO and under such conditions NO inhibition might actually be beneficial." We propose to mimic the postmenopausal state in experimental animals by ovariectomy (OVX). We propose to mimic endothelial dysfunction by pharmacological means by administering animals an inhibitor of NO synthesis. The hypothesis will be tested under three specific aims.