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.

R03AG018999

2000-09-30

2002-08-31