Eliciting Estrogen's Protective Vascular Effects

激发雌激素的保护性血管作用

• 批准号: 9474239
• 负责人: Sarah H. Lindsey
• 金额: $ 3.43万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9474239
• 关键词: Adult; Aging; Agonist; Antioxidants; Attenuated; Binding Proteins; Biological; Biomechanics; Biomedical Engineering; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cells; Central Artery; Clinical; Clinical Trials; Collaborations; Complex; Computer Simulation; Data; Disease; Down-Regulation; EFRAC; Electron Spin Resonance Spectroscopy; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Therapy; Estrogens; Extracellular Matrix; Female; Free Radicals; Frequencies; GPER gene; Genetic; Glycosaminoglycans; Gold; Heart failure; Hormones; Hypertension; In Vitro; Knockout Mice; Life; Longevity; Measurement; Measures; Mechanics; Membrane; Menopause; Methods; Mitochondria; Modeling; Molecular; Mus; Muscle Cells; Myography; NADP; Organ; Outcome; Ovariectomy; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Population; Postmenopause; Production; Pulse Pressure; Quality of life; Reactive Oxygen Species; Receptor Activation; Reporting; Resolution; Role; SOD2 gene; Sampling; Signal Transduction; Sodium Chloride; Techniques; Ultrasonography; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Woman; Women' s Health; arterial stiffness; cardiovascular health; cardiovascular risk factor; digital; hormone therapy; improved; in vivo; innovation; knock-down; mathematical model; mechanical properties; men; mouse model; neglect; non-genomic; novel; novel therapeutics; pressure; receptor; receptor downregulation; receptor expression; response; targeted treatment; therapeutic target; treatment strategy; versican

PROJECT SUMMARY Menopause increases arterial stiffness which accelerates end organ damage, increases cardiac afterload, and promotes heart failure with preserved ejection fraction, a disease twice as common in women than men. Since the Women's Health Initiative reported that postmenopausal estrogen therapy induces adverse vascular effects, new drugs are needed to protect aging women from cardiovascular disease. We propose that selective therapies targeting the recently-discovered G protein-coupled estrogen receptor (GPER) will reduce cardiovascular risk in postmenopausal women. Our preliminary data indicate a crucial role for GPER in vascular protection: GPER activation attenuates salt-induced vascular remodeling while GPER deletion increases pulse pressure, an in vivo indicator of arterial stiffness. This project will demonstrate that GPER protects the vasculature through a novel molecular mechanism by which nongenomic estrogen signaling decreases ROS and attenuates glycosaminoglycans (GAGs) in the extracellular matrix, thereby preserving the mechanical properties of central arteries and decreasing pulse wave velocity. Moreover, an aging-induced decrease in vascular GPER expression promotes adverse responses to estrogen but can be corrected with selective therapeutics that target this receptor. We propose that vascular GPER protects from arterial stiffness, and targeting this receptor will improve responses to postmenopausal hormone therapy. Using a combination of in vivo, ex vivo, and in vitro approaches will allow us to assess our hypothesis in multiple ways. High-frequency ultrasound will allow in vivo measurement of pulse wave velocity, the gold standard for assessing vascular stiffness. As opposed to traditional uniaxial pressure myography, biaxial mechanical phenotyping performed in collaboration with a biomedical engineer will allow the use of computational models to delineate the contributing factors for arterial stiffness. ROS measurements will be obtained using electron spin resonance spectroscopy, a direct and sensitive approach for quantifying free radicals in biological samples. Moreover, an inducible, cell-specific GPER knockout mouse model will allow us to specifically assess the impact of decreased vascular GPER expression during adulthood on the response to nonselective estrogen therapy.

项目总结 更年期会增加动脉僵硬，加速终末器官损伤，增加心脏后负荷， 并在保留射血分数的情况下促进心力衰竭，这种疾病在女性中的发病率是男性的两倍。 自从《妇女健康倡议》报道绝经后雌激素治疗会导致不良血管 为了提高疗效，需要新的药物来保护老年妇女免受心血管疾病的影响。我们建议有选择性地 针对最近发现的G蛋白偶联雌激素受体(GPER)的治疗将减少 绝经后妇女的心血管风险。 我们的初步数据表明GPER在血管保护中起着关键作用：GPER的激活减弱 盐诱导的血管重塑同时GPER缺失增加脉压，这是动脉的体内指标 僵硬。本项目将展示GPER通过一种新的分子保护血管系统 非基因组雌激素信号降低ROS和抑制糖胺聚糖的机制 (GAG)在细胞外基质中，从而保持中央动脉和 脉搏波速度减慢。此外，衰老导致的血管GPER表达减少促进了 对雌激素的不良反应，但可以通过针对这种受体的选择性治疗来纠正。 我们认为，血管GPER保护动脉僵硬，靶向该受体将 改善对绝经后激素治疗的反应。使用体内、体外和体内的组合 体外实验方法将允许我们以多种方式评估我们的假设。高频超声波将允许 活体测量脉搏波速度，这是评估血管僵硬的金标准。而不是 传统的单轴加压肌肉造影术，与 生物医学工程师将允许使用计算模型来描绘动脉粥样硬化的影响因素 僵硬。ROS的测量将使用电子自旋共振光谱，直接和 生物样品中自由基定量的灵敏方法。此外，一种可诱导的、细胞特异性的 GPER基因敲除小鼠模型将使我们能够专门评估血管GPER降低的影响 成年期对非选择性雌激素治疗反应的表达。