Biological Mechanisms of Vascular Dysfunction with Age and Estrogen Deficiency

年龄和雌激素缺乏导致血管功能障碍的生物学机制

• 批准号: 8732808
• 负责人: Kerrie Moreau
• 金额: $ 65.08万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732808
• 关键词: Acute; Address; Age; Aging; Anabolism; Antioxidants; Ascorbic Acid; Award; Back; Biological; Biological Availability; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Data; Defect; Development; Endothelial Cells; Endothelium; Estrogens; Event; Experimental Models; Free Radicals; Functional disorder; Future; Gonadotropin Hormone Releasing Hormone; Health; Hormonal; Hormonal Change; Hormone Antagonists; Hormones; In Vitro; Infusion procedures; Injury; Intervention; Lead; Maintenance; Measures; Mediating; Mediator of activation protein; Menopause; Methods; Molecular; Nitric Oxide; Oral; Ovarian; Ovarian Ablation; Oxidative Stress; Perimenopause; Peroxonitrite; Placebos; Plasma; Plasma Cells; Postmenopause; Premenopause; Prevention; Process; Production; Progress Reports; Proteins; Reactive Oxygen Species; Research; Role; Source; Staging; Supplementation; Testing; Therapeutic; Therapeutic Intervention; Vascular Endothelial Cell; Woman; brachial artery; cardiovascular disorder risk; cell growth regulation; cofactor; design; follow-up; human NOS3 protein; improved; insight; men; prevent; protein expression; public health relevance; research study; response; restoration; sex; tetrahydrobiopterin

DESCRIPTION (provided by applicant): This competing renewal application (R01 AG027678) will extend and expand on research that was responsive to RFA-AG-05-008 "Biology of the Perimenopause: Impact on Health and Aging." Findings from the first award period demonstrate that: 1) endothelial function (endothelium-dependent dilation; EDD) becomes more impaired with declining ovarian function, and 2) oxidative stress is one of the underlying mechanisms involved in impaired EDD. The global aim of this renewal application is to determine the role of tetrahydrobiopterin (BH4; an essential cofactor for endothelial nitric oxide synthase (eNOS) and nitric oxide [NO] synthesis) and eNOS uncoupling as potential mediators of oxidative stress-related endothelial dysfunction with the menopause transition and aging in women. This will be assessed in Aim 1 using cross-sectional comparisons of healthy pre-, peri- and postmenopausal women. Endothelial function will be measured under basal conditions and following an acute increase in BH4. Aim 2 will expand on the cross-sectional comparisons by using short-term (10 days) suppression of estrogen (E2) using gonadotropin releasing hormone antagonist [GnRHant] in pre-and perimenopausal women to determine the age-independent effects of E2 on EDD. Aim 3 will examine the co-administration of BH4 and an anti-oxidant (ascorbic acid; AA) for the restoration of EDD. The primary hypotheses are that the reduced EDD in peri- and postmenopausal women, and in pre- and perimenopausal women following short-term E2 suppression, will increase in response to oral BH4. Secondary hypotheses predict that the reduced EDD in peri- and postmenopausal women (at baseline and with E2 suppression) will be associated with plasma and endothelial cell protein markers of BH4 biosynthesis and oxidative stress in vascular endothelial cells. A tertiary hypothesis is that the co-administration of BH4 an AA will restore EDD in peri-and postmenopausal women to levels of premenopausal women. To test these hypotheses, brachial artery EDD will be measured in: 1) pre-and early perimenopausal women before and after short-term E2 suppression (GnRHant) and add-back of either transdermal E2 or placebo; and 2) postmenopausal women at baseline. To determine possible mechanisms for endothelial dysfunction, EDD will also be measured after oral BH4 supplementation alone and during AA infusion. Insight into the molecular events underlying the decrease in EDD will be determined by assessing the changes in endothelial cell expression of proteins involved in the regulation of cellular and systemic adaptations to E2 deficiency including BH4 biosynthesis and oxidative stress. [The results from this research should expand our earlier findings and elucidate further the mechanisms that mediate endothelial dysfunction across the stages of the menopause transition and whether these processes are triggered by E2 deficiency. Understanding these mechanistic defects will help to inform the critical window of intervention and guide future sex-specific interventions and therapies for the maintenance of vascular function and prevention of future cardiovascular diseases.]

描述（由申请人提供）：该竞争性续展申请 (R01 AG027678) 将扩展和扩展响应 RFA-AG-05-008“围绝经期生物学：对健康和衰老的影响”的研究。第一个奖励期的研究结果表明：1）内皮功能（内皮依赖性扩张；EDD）随着卵巢功能的下降而更加受损，2）氧化应激是 EDD 受损的潜在机制之一。这项更新申请的全球目标是确定四氢生物蝶呤（BH4；内皮一氧化氮合酶 (eNOS) 和一氧化氮 [NO] 合成的重要辅助因子）和 eNOS 解偶联作为氧化应激相关内皮功能障碍的潜在介质的作用。女性的更年期过渡和衰老。这将在目标 1 中通过健康绝经前、围绝经期和绝经后妇女的横断面比较进行评估。将在基础条件下和 BH4 急剧增加后测量内皮功能。目标 2 将通过在绝经前和围绝经期女性中使用促性腺激素释放激素拮抗剂 [GnRHant] 短期（10 天）抑制雌激素 (E2) 来扩展横断面比较，以确定 E2 对 EDD 的年龄独立影响。目标 3 将检查 BH4 和抗氧化剂（抗坏血酸；AA）的共同给药对 EDD 的恢复。主要假设是，围绝经期和绝经后女性以及绝经前和围绝经期女性在短期 E2 抑制后 EDD 减少，口服 BH4 后 EDD 会增加。次要假设预测，围绝经期和绝经后女性 EDD 的减少（在基线和 E2 抑制的情况下）将与 BH4 生物合成的血浆和内皮细胞蛋白标记物以及血管内皮细胞的氧化应激有关。第三个假设是，BH4 和 AA 的共同给药将使围绝经期和绝经后女性的 EDD 恢复到绝经前女性的水平。为了检验这些假设，将测量以下人群的肱动脉 EDD：1) 短期 E2 抑制 (GnRHant) 和透皮 E2 或安慰剂加回之前和之后的围绝经前和早期女性； 2) 基线绝经后妇女。为了确定内皮功能障碍的可能机制，还将在单独口服 BH4 补充剂后和输注 AA 期间测量 EDD。通过评估内皮细胞表达的蛋白质的变化来深入了解 EDD 减少的分子事件，这些蛋白质参与调节细胞和系统对 E2 缺乏的适应，包括 BH4 生物合成和氧化应激。 [这项研究的结果应该扩展我们早期的发现，并进一步阐明介导更年期过渡阶段内皮功能障碍的机制，以及这些过程是否是由 E2 缺乏引发的。了解这些机制缺陷将有助于了解干预的关键窗口，并指导未来针对维持血管功能和预防未来心血管疾病的针对性别的干预措施和治疗。]