Biological Mechanisms of Arterial Stiffening With Age and Estrogen Deficiency

动脉硬化随年龄和雌激素缺乏的生物学机制

• 批准号: 7067948
• 负责人: Kerrie Moreau
• 金额: $ 26.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067948
• 关键词: NAD(H) phosphate; aging; angiotensin II; angiotensin receptor; ascorbate; carotid artery; clinical research; endothelin; estradiol; estrogen receptors; female; gene expression; glutathione peroxidase; gonadotropin releasing factor; hormone inhibitor; hormone regulation /control mechanism; hormone therapy; human subject; menopause; nitric oxide synthase; oxidative stress; postmenopause; vascular endothelium; vascular resistance; vasodilation; women' s health

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.

描述（由申请人提供）：该 R01 提案的目的是确定女性性激素（特别是雌二醇 (E2)）的丧失导致与年龄相关的大动脉顺应性下降的关键功能机制。总体假设是，在绝经前和围绝经期女性中，基础大动脉顺应性会因急性性激素抑制而降低，部分原因是血管内皮依赖性血管舒张张力降低，部分原因是血管氧化应激的发生。然而，在性激素抑制期间给予E2将减少血管氧化应激，改善内皮血管舒张张力并将动脉顺应性恢复至基础水平。第二和第三假设是，性激素抑制和 E2 引起的动脉顺应性和血管舒张功能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）、血管收缩剂（内皮素-1）和雌激素受体 α （ERα）。为了检验这些假设，将对健康的绝经前、围绝经期和绝经后妇女在急性性激素抑制（促性腺激素释放激素拮抗剂 [GnRHant]）前后进行研究，无论是否有 E2 回加疗法。 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 回加干预将使我们能够分离出 E2 的独立影响。将使用一种新颖的转化研究技术来深入了解介导大动脉顺应性降低的分子机制，以确定血管内皮细胞蛋白质表达的变化，这些基因涉及细胞和系统对衰老和性激素缺乏（包括氧化应激）的适应的调节、一氧化氮生物利用度和有效的转录因子 ERalpha 蛋白。这些结果将为了解性激素缺乏调节女性在绝经期过渡时与年龄相关的大动脉顺应性降低的综合生物学机制提供新的见解。