CALCITONIN GENE RELATED PEPTIDE AND AGING

在美国，心血管疾病是主要的死亡原因。流行病学研究表明，绝经后妇女高血压的发病率增加。虽然激素替代疗法是减少这种疾病的最有效的治疗方法，但导致这种疾病的机制尚不清楚。我们认为降钙素基因相关肽(CGRP)在这种机制中起着关键作用。降钙素基因相关肽(CGRP)是背根节(DRG)神经元合成的一种有效的血管扩张剂，参与调节血液流向重要器官。研究表明，降钙素基因相关肽的变化可能参与了一系列心血管疾病的病理生理过程，包括冠状动脉疾病和高血压。最近，我们使用卵巢切除(OVX；卵巢激素耗竭)动物作为女性绝经后状态的模型，以确定卵巢切除后是否以类固醇激素依赖的方式减少了CGRP的合成和血管扩张作用。结果表明，雌激素(E)和孕酮(P)对成年去势大鼠降压作用有增强作用。我们进一步报道了E和P都以时间和剂量依赖的方式刺激去卵巢大鼠神经元CGRP的表达。此外，我们还发现雌性类固醇激素显著增加了成年OVX大鼠循环中的Corp水平。这些研究表明，背根神经节增加CGRP的神经元表达可能至少部分介导性激素的心血管保护作用。在本项目中，我们将在老年雌性大鼠身上测试这一假设，在老年雌性大鼠中，类固醇激素类似于绝经后的人类，随着年龄的增长而减少。本研究的目的是首先确定老年大鼠皮质神经元的表达及其降压效应是否发生改变，然后确定类固醇激素在这一现象中所起的作用。这些研究将为绝经后老年妇女提供相关证据，在这些妇女中，Corp可能是类固醇激素调节血压的重要因素。此外，我们的初步研究表明，长期卵巢切除后，17β-雌二醇显著增加老年大鼠循环CGRP的水平。我们还希望将这些研究扩展到去卵巢的老年大鼠，以确定CGRP的血管扩张效应是否受到类固醇激素拮抗治疗的调节。这些研究对于评估类固醇激素升高的CGRP水平是否在减少老年女性绝经几年后的典型心血管疾病方面起到了作用。

Cardiovascular disease is the leading cause of death in the United States. Epidemiologic studies indicate that the morbidity of hypertension in women increases after menopause. Although hormonal replacement is the most useful therapy to reduce this disease, the mechanisms responsible for this disorder are not well understood. We propose that the calcitonin gene-related peptide (CGRP) plays a critical role in such mechanisms. CGRP, a potent vasodilator synthesized in dorsal root ganglia (DRG) neurons, is involved in the regulation of blood flow to vital organs. Reports indicate that alterations of CGRP may be involved in the pathophysio1ogy of a spectrum of cardiovascular diseases, including coronary artery disease and hypertension. Recently, we have employed ovariectomized (ovx; depletion of ovarian hormones) animals as a model of postmenopausal state in women in order to determine whether CGRP synthesis and vasodilator effects are decreased after ovariectomy in a steroid hormone-dependent fashion. Our results showed that the hypotensive effects of CGRP are enhanced by estrogen (E) and progesterone (P) in adult ovx rats. We further reported that both E and P stimulate neuronal expression of CGRP in a time- and dose-dependent manner in ovx rats. Furthermore, we found that circulating levels of CORP are significantly increased by female sex steroid hormones in adult ovx rats. These studies suggest that increased neuronal expression of CGRP by DRG may mediate, at least in part, the cardiovascular protective effects of sex hormones. In the present project, we will test this hypothesis in aged female rats in which steroid hormones, similarly to post-menopausal humans, decease with age. The goal of this proposal is to first determine whether neuronal expression of CORP and its hypotensive effects are altered in aged rats and to then determine the role played in this phenomenon by steroid hormones. These studies will provide evidence relevant to post menopausal aged women, where CORP may be an important factor mediating steroid hormone effects on blood pressure regulation. Furthermore, our preliminary studies indicate that circulatory levels of CGRP are significantly increased by 17beta-estradiol in aged rats after long-term ovariectomy. We also wish to extend these studies to ovariectomized aged rats in order to determine whether the perturbations in vasodilatory effects of CGRP are modulated by steroid hormone rep1acement treatment. These studies are important for the assessing whether increased levels of CGRP by steroid hormones play a role in decreasing cardiovascular disorders that are typical of aged women after several years of menopause.