Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

描述（由申请方提供）：本R 01提案的目的是确定女性性激素（特别是雌二醇（E2））的丧失导致大动脉顺应性年龄相关性降低的关键功能机制。总的假设是，基底大动脉顺应性将减少，在响应急性性激素抑制在绝经前和围绝经期妇女由于部分介导的血管内皮依赖性血管舒张张力的减少，部分，血管氧化应激的发展。然而，在性激素抑制期间给予E2将降低血管氧化应激，改善内皮血管舒张张力并将动脉顺应性恢复至基础水平。第二和第三假设是动脉顺应性和血管舒张功能随性激素抑制和E2的变化将分别与血管内皮细胞蛋白表达的不利和有利变化相关，包括氧化剂（例如，NADPH）和抗氧化剂（例如，谷胱甘肽过氧化物酶）酶、血管收缩剂（内皮素-1）和雌激素受体α（ER α）。为了检验这些假设，将在急性性激素抑制（促性腺激素释放激素拮抗剂[GnRHant]）治疗前后（伴或不伴E2反加治疗）对健康绝经前、绝经后和绝经后女性进行研究。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反加干预将使我们能够分离E2的独立作用。深入了解介导大动脉顺应性降低的分子机制，将获得使用一种新的翻译研究技术，以确定血管内皮细胞蛋白表达的变化，参与调节细胞和全身适应衰老和性激素缺乏症，包括氧化应激，一氧化氮生物利用度，和有效的转录因子ER α蛋白的基因。这些结果应该提供新的见解，综合性的生物学机制，性激素缺乏症调节与年龄相关的减少大动脉顺应性的妇女，因为他们通过更年期过渡。

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.