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提案的目的是确定关键功能机制，通过这些机制，女性性激素（尤其是雌二醇（E2））的丧失有助于大动脉依从性的年龄相关性下降。总体假设是，基础大动脉依从性将响应于急性性激素抑制急性性激素的抑制前和绝经性症状女性，部分原因是血管内皮依赖性的血管舒张性张力降低，部分是由于血管氧化应激的发展而介导的。但是，在性激素抑制期间的E2给药将减少血管氧化应激，改善内皮血管舒张性张力并恢复动脉依从性至基础水平。 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）和雌激素受体α（Eralpha）。为了检验这些假设，将在有或没有E2添加补充治疗的情况下，在急性性激素抑制之前和之后对健康前，周期和绝经后妇女进行研究。 gnrhant干预将使我们能够研究与性激素缺乏症相关的直接机制，而E2添加式干预将使我们能够隔离E2的独立效应。洞悉介导的分子机制介导的大动脉依从性下降将使用一种新型的翻译研究技术获得，以确定参与调节细胞和全身性适应性激素缺乏症的基因的血管内皮细胞蛋白表达的变化，包括氧化应激，包括氧化氧化物的氧化氧化物生物元素的蛋白质和POTERTER CRIPTION和POTERTERICTIC。结果应提供对性激素缺乏症的综合生物学机制的新见解，从而调节女性在更年期过渡时大型动脉依从性的年龄相关性降低。