Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

描述(由申请人提供)：本R01提案的目的是确定女性性激素的丧失，特别是雌二醇(E2)的丧失，导致与年龄相关的大动脉顺应性下降的关键作用机制。总体假设是，绝经前和围绝经期妇女的基础大动脉顺应性将因急性性激素抑制而降低，部分原因是血管内皮依赖的血管扩张张力减少，部分是由于血管氧化应激的发展。然而，在性激素抑制期间给予E2将减少血管氧化应激，改善内皮血管舒张性，并将动脉顺应性恢复到基础水平。第二个和第三个假设是，随着性激素抑制和雌二醇的作用，动脉顺应性和血管扩张功能的改变将分别与血管内皮细胞蛋白表达的不利和有利变化有关，血管内皮细胞蛋白表达包括氧化剂(例如NADPH)和抗氧化剂(例如谷胱甘肽过氧化物酶)、血管收缩因子(内皮素-1)和雌激素受体α(ERpha)。为了验证这些假设，健康的绝经前、围绝经期和绝经后妇女将在急性性激素抑制(促性腺激素释放激素拮抗剂[GnRHant])加或不加E2治疗前后进行研究。GnRHant干预将使我们能够研究与性激素缺乏相关的直接机制，而E2加回干预将使我们能够分离出E2的独立作用。利用一种新的翻译研究技术来确定参与调节细胞和系统对衰老和性激素缺乏的适应的基因的血管内皮细胞蛋白表达的变化，包括氧化应激、一氧化氮的生物利用度和强大的转录因子ERpha蛋白，将深入了解大动脉顺应性下降的分子机制。这些结果将为综合生物学机制提供新的见解，性激素缺乏通过调节女性更年期过渡期间与年龄相关的大动脉顺应性下降。

DESCRIPTION (provided by applicant): The purpose of this R01 proposal is to determine the key functional mechanisms by which the loss of female sex hormones, particularly estradiol (E2), contribute to the age-related decrease in large artery compliance. The overall hypothesis is that basal large artery compliance will decrease in response to acute sex hormone suppression in pre- and perimenopausal women due in part to a decrease in vascular endothelial-dependent vasodilatory tone mediated, in part, to the development of vascular oxidative stress. However, E2 administration during sex hormone suppression will decrease vascular oxidative stress, improve endothelial vasodilatory tone and restore arterial compliance to basal levels. Secondary and tertiary hypotheses are that the changes in arterial compliance and vasodilatory function with sex hormone suppression and E2 will be related to unfavorable, and favorable, respectively, changes in vascular endothelial cell protein expression including oxidant (e.g., NADPH) and antioxidant (e.g., glutathione peroxidase) enzymes, vasoconstrictors (endothelin- 1), and estrogen receptor alpha (ERalpha). To test these hypotheses, healthy pre-, peri-, and postmenopausal women will be studied at before and following acute sex hormone suppression (gonadotropin releasing hormone antagonist [GnRHant]) with or without E2 add-back therapy. The GnRHant intervention will enable us to study the direct mechanisms associated with sex hormone deficiency and the E2 add-back intervention will enable us to isolate the independent effects of E2. Insight into the molecular mechanisms mediating the decrease in large artery compliance will be obtained using a novel translational research technique to determine changes in vascular endothelial cell protein expression of genes involved in the regulation of cellular and systemic adaptations to aging and sex hormone deficiency including oxidative stress, nitric oxide bioavailability, and the potent transcription factor ERalpha proteins. The results should provide new insight into the integrative biological mechanisms by which sex hormone deficiency modulates the age-related reduction in large artery compliance in women as they transition through the menopause.