Ovarian Hormone Loss and Perivascular Fat

卵巢激素丢失和血管周围脂肪

• 批准号: 10018620
• 负责人: HONG JI
• 金额: $ 19.44万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018620
• 关键词: Adipose tissue; Adverse effects; Age; Ancillary Study; Anti-Inflammatory Agents; Aorta; Arteries; Bilateral; Bilateral oophorectomy; Biological Markers; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinical Research; Clinical Trials; Clinical Trials Design; Conflict (Psychology); Coronary; Development; Diabetes Mellitus; Estradiol; Exhibits; Fatty acid glycerol esters; Follicle Stimulating Hormone; Functional disorder; Generations; Health; Heart; Hormonal; Hormone replacement therapy; Hormone use; Hormones; Hypertension; Inflammation; Lead; Light; Location; Menopause; Mesentery; Microcirculation; Nitric Oxide; Obesity; Ovarian hormone; Ovariectomy; Oxidative Stress; Parametrial; Pathologic; Perimenopause; Peripheral; Peripheral Blood Mononuclear Cell; Pituitary Hormones; Play; Postmenopause; Premature Ovarian Failure; Rattus; Regimen; Research; Research Design; Resistance; Retroperitoneal Space; Risk Factors; Role; Salpingo-Oophorectomy; Structure; Study of Women' s Health Across the Nation; Superoxides; Target Populations; Testing; Therapeutic; Tissues; Vascular Diseases; Visceral fat; Woman; arteriole; blood pressure regulation; cardioprotection; cardiovascular disorder risk; cardiovascular health; experience; hormone deficiency; hormone regulation; new therapeutic target; novel therapeutic intervention; preservation; protective effect; relaxing factor; restoration; vascular bed

Most women will experience ovarian hormone loss in their lifetime due to menopause or earlier due to other elective bilateral salpingo-oophorectomy, premature ovarian failure or other causes. Many studies indicate ovarian hormone deficiency is a major risk factor for developing cardiovascular disease (CVD) and CVD is the number one cause of death in women. Conflicting studies over the cardiovascular benefits of hormone replacement therapy (HRT) reflect differing HRT regimens and/or differing subpopulations of postmenopausal women. Thus, a fuller understanding of the biology underlying the effects of ovarian hormone loss and HRT on women’s cardiovascular health is required to comprehensively inform women's decisions regarding the use of HRT especially since HRT is contraindicated in some women. This increased understanding will also facilitate efforts towards developing new therapeutic strategies for women when they reach this point in their lives. Blood vessels are surrounded by perivascular adipose tissue (PVAT), which we and others have shown can modulate vascular function. There is a growing appreciation that adipose tissue has distinct functions depending upon the location of the adipose depot. Thus, we hypothesize that PVAT will exhibit vessel and adipose depot-specific functions. Our research also shows that the vascular protective effects of PVAT on rat mesenteric vessels are lost after ovariectomy; however, it is not known whether this loss in ovarian hormone protection is also observed in other vascular beds and if not, whether differences in ovarian hormone regulation of PVAT function is due to vessel and/or adipose depot-specific effects. Our findings also suggest that restoration of PVAT function could reduce the risk of CVD induced by ovarian hormone loss; however, the HRT conditions under which PVAT function would be protected after ovarian hormone loss remains unclear. Thus, elucidating how ovarian hormone dysfunction and HRT modulates PVAT activity as a function of vascular bed and adipose depot could lead to the development of new PVAT-focused therapeutics for treating vascular dysfunction induced by ovarian hormone loss. These studies led to our overall hypothesis that in order for an HRT regimen in a target population to be cardioprotective, it must preserve the vascular protective effects of PVAT on arterioles in the microcirculation since these resistance vessels play a major role in regulating blood pressure. Aim 1 will determine the role of 17b-estradiol (E2) and follicle stimulating hormone (FSH) in PVAT modulation of mesenteric arteriole vascular reactivity and nitric oxide (NO) and superoxide (O2-) generation. Aim 2 will determine the effect of PVAT modulation of vascular reactivity as a function of the vascular bed and adipose depot. Exploratory Aim 3 will identify biomarkers in circulating peripheral blood mononuclear cells (PBMC) that correlate with altered PVAT function under the experimental conditions. We hypothesize that identified biomarkers will inform clinical trials designed to optimize the composition, timing and duration of HRT regimens. !

大多数女性在一生中都会因更年期或更早因其他原因而经历卵巢激素的流失。 许多研究表明，选择性双侧输卵管卵巢切除术、卵巢早衰或其他原因。 卵巢激素缺乏是发生心血管疾病（CVD）的主要危险因素，而CVD是 关于激素对心血管益处的研究相互矛盾。 替代疗法 (HRT) 反映了不同的 HRT 方案和/或不同的绝经后亚群 因此，更全面地了解卵巢激素损失和 HRT 对女性的影响的生物学原理。 需要了解女性心血管健康，以全面告知女性有关使用药物的决定 激素替代疗法（HRT），特别是因为激素替代疗法（HRT）在某些女性中是禁忌的，这种增加的了解也将有利于促进。 当女性达到生命的这一点时，为她们努力制定新的治疗策略。 血管被血管周围脂肪组织（PVAT）包围，我们和其他人已经证明它可以调节 人们越来越认识到脂肪组织具有不同的功能，具体取决于血管功能。 因此，我们约定 PVAT 将展示特定于血管和脂肪库的位置。 我们的研究还表明PVAT对大鼠肠系膜血管具有血管保护作用。 卵巢切除术后丢失；然而，尚不清楚是否也观察到这种卵巢激素保护的丧失。 在其他血管床中，如果没有，卵巢激素对 PVAT 功能调节的差异是否是由于 我们的研究结果还表明，PVAT 功能的恢复可以。 降低卵巢激素丢失引起的 CVD 风险；然而，PVAT 的 HRT 条件 因此，卵巢激素如何保护卵巢激素的功能仍不清楚。 功能障碍和 HRT 调节 PVAT 活性作为血管床和脂肪库的功能可能导致 开发新的以 PVAT 为重点的疗法，用于治疗卵巢激素引起的血管功能障碍 这些研究得出了我们的总体假设：为了在目标人群中实施 HRT 治疗方案， 心脏保护作用，必须保留 PVAT 对微循环小动脉的血管保护作用 因为这些阻力血管在调节血压方面发挥着重要作用，目标 1 将决定其作用。 17b-雌二醇 (E2) 和卵泡刺激素 (FSH) 在 PVAT 调节肠系膜小动脉血管中的作用 目标 2 将决定 PVAT 的效果。 探索性目标 3 将调节血管反应性作为血管床和脂肪库的函数。 识别循环外周血单核细胞 (PBMC) 中与 PVAT 改变相关的生物标志物 我们发现，已识别的生物标志物将为临床试验提供信息。 旨在优化 HRT 方案的组成、时机和持续时间。 ！