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，特别是雌二醇（E2）的丧失导致大动脉顺应性年龄相关下降的关键功能机制。总的假设是，在绝经前和围绝经期妇女急性性激素抑制的情况下，基底大动脉顺应性会降低，部分原因是血管内皮依赖性血管舒张张力介导的减少，部分原因是血管氧化应激的发展。然而，在性激素抑制期间给予E2会降低血管氧化应激，改善内皮血管舒张张力，使动脉顺应性恢复到基础水平。第二假说和第三假说认为，性激素抑制和E2对动脉依从性和血管舒张功能的影响分别与血管内皮细胞蛋白表达的不利和有利变化有关，包括氧化剂（如NADPH）和抗氧化剂（如谷胱甘肽过氧化物酶）、血管收缩剂（内皮素- 1）和雌激素受体α (er - α)。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]）前后进行研究，同时进行E2加回治疗或不加回治疗。GnRHant干预将使我们能够研究与性激素缺乏相关的直接机制，E2加回干预将使我们能够分离E2的独立影响。通过一种新的翻译研究技术，研究人员将深入了解大动脉顺应性降低的分子机制，以确定血管内皮细胞蛋白表达的变化，这些基因参与调节细胞和系统对衰老和性激素缺乏的适应，包括氧化应激、一氧化氮生物利用度和有效的转录因子erα蛋白。这些结果应该为性激素缺乏调节绝经期妇女大动脉顺应性随年龄减少的综合生物学机制提供新的见解。

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.