ROLE OF NO AND ESTRADIOL IN AGING AND ATHEROGENESIS

在女性衰老过程中，会发生两个影响血管系统的重要变化。第一种是绝经，与雌激素戒断有关，另一种是内皮功能障碍，表现为内皮依赖性血管舒张减少，可能是内皮细胞产生一氧化氮减少的反映。这两种变化可能是相互独立的，也可能是相互联系的。我们和其他人已经证明雌二醇（E2）增加NO的产生。因此，在衰老和绝经期间内皮功能障碍表现为内皮依赖性血管舒张减少和NO产生减少，这可能仅仅是E2停药的基础。绝经后妇女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，在研究的第一年，雌激素和黄体酮联合应用于有充分证据证明冠心病的妇女与第二次冠状动脉事件的发生率增加有关。在这项研究中，没有一组女性单独接受E2。因此，E2在动脉粥样硬化发生中的调节作用，一旦疾病建立是未知的。同样，绝经后妇女偶尔给予睾酮(t)以增加其性功能，但t对动脉粥样硬化的影响尚不清楚。要测试的总体假设是，“仅仅是E2或T的减少就会导致NO合成的减少，从而导致血管壁的促炎反应，导致动脉粥样硬化早期的变化。”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，NO抑制实际上可能是有益的。”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。我们建议通过给动物注射一氧化氮合成抑制剂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.