ROLE OF NO AND ESTRADIOL IN AGING AND ATHEROGENESIS

在女性衰老过程中，发生了两个影响血管系统的重要变化。第一种是与雌激素戒断相关的绝经，另一种是内皮功能障碍，表现为内皮依赖性血管舒张的减少，可能是内皮细胞产生NO减少的反映。这两种变化可以是相互独立的，也可以是相互联系的。我们和其他人已经证明，雌二醇（E2）增加NO的产生。因此，在衰老和绝经期间观察到的内皮功能障碍，表现为内皮依赖性血管舒张的减少和NO产生的减少，可以仅根据E2的单独撤退来解释。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发挥有益作用的确切机制尚不清楚。另一方面，最近的一项研究表明，与安慰剂组相比，对有明确记录的冠状动脉疾病的女性给予雌激素和孕激素的组合与研究第一年中第二次冠状动脉事件发生率的增加有关。在这项研究中，没有一组妇女单独接受E2。因此，一旦疾病确立，E2在调节动脉粥样硬化形成中的作用尚不清楚。同样，绝经后妇女偶尔给予睾酮（t）以增加其性功能，但T对动脉粥样硬化形成的影响尚不清楚。待检验的总体假设是，“仅仅E2或T的撤回导致NO合成的减少，从而导致血管壁的促炎反应，导致动脉粥样硬化形成早期的变化。一个必然的结果是，动脉粥样硬化过程的极端可能会增加生产的OONO和在这种情况下，NO抑制可能实际上是有益的。“我们建议通过卵巢切除术（OVX）来模拟实验动物的绝经后状态。我们建议通过药理学手段通过给动物施用NO合成抑制剂来模拟内皮功能障碍。将在三个具体目标下检验这一假设。

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.