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）：这种竞争性续约申请（R01 AG027678）将扩展并扩展对RFA-AG-05-008响应的研究，“围绝经期生物学：对健康和衰老的影响”。第一个奖项期的发现表明：1）内皮功能（内皮依赖性扩张； EDD）变得更加受卵巢功能的损害，而2）氧化应激是EDD受损涉及的基本机制之一。这种更新应用的全球目的是确定四氢无菌蛋白酶的作用（BH4；内皮氮氧化物合酶（ENOS）和一氧化氮[no]合成）和ENOS与氧化应激的内皮型型甲壳虫的潜在介体不合偶联的作用（NO NO]合成）和ENOS不合偶联。这将在AIM 1中使用健康前，周期和绝经后妇女的横断面比较来评估。内皮功能将在基础条件下和BH4急性增加之后测量。 AIM 2通过使用短期（10天）抑制雌激素（E2）的促性腺激素释放激素拮抗剂[Gnrhant]来确定E2对EDD的E2对EDD的年龄无关效应，从而扩展了AIM 2。 AIM 3将检查BH4和抗氧化剂（抗坏血酸； AA）的共同给药以恢复EDD。主要的假设是，在短期E2抑制后，绝经后和绝经后妇女的EDD以及前后妇女的EDD减少，对口服BH4的响应将增加。次要假设预测，绝经后妇女和绝经后妇女的EDD（基线和E2抑制）将与BH4生物合成的血浆和内皮细胞蛋白标记物有关，血管内皮细胞中的EDD和氧化应激。第三个假设是，BH4 AA的共同给药将使绝经后妇女的EDD恢复到绝经前妇女的水平。为了检验这些假设，将在：1）短期E2抑制（Gnrhant）之前和之后测量的肱动脉EDD和早期的临床前妇女和透皮E2或安慰剂或安慰剂的添加后背； 2）基线后绝经后妇女。为了确定内皮功能障碍的可能机制，也将单独和在AA输注期间进行口服BH4补充后测量EDD。通过评估参与调节细胞和全身适应E2缺乏症的蛋白质的内皮细胞表达的变化，可以确定EDD降低的分子事件的洞察力，包括BH4生物合成和氧化应激。 [这项研究的结果应扩大我们的早期发现，并进一步阐明在更年期过渡阶段介导内皮功能障碍的机制，以及这些过程是否是由E2缺乏触发的。了解这些机械缺陷将有助于告知干预的关键窗口，并指导未来的性别特定干预措施和疗法维持血管功能和预防未来的心血管疾病。]