Eliciting Estrogen's Protective Vascular Effects

激发雌激素的保护性血管作用

• 批准号: 9318676
• 负责人: Sarah H. Lindsey
• 金额: $ 35.61万
• 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/9318676
• 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.

项目摘要 更年期会增加动脉刚度，从而加速最终器官损伤，增加心脏后负荷， 并通过保留的射血分数来促进心力衰竭，这种疾病在女性中的疾病是男性的两倍。 自从妇女的健康倡议报道，绝经后雌激素治疗会诱导不良血管 效果，需要新药来保护衰老的妇女免受心血管疾病的侵害。我们建议选择性 针对最近发现的G蛋白偶联雌激素受体（GPE）的疗法将减少 绝经后妇女的心血管风险。 我们的初步数据表明GPE在血管保护中的至关重要：GPER激活减弱 盐诱导的血管重塑而GPER缺失会增加脉压，这是动脉的体内指标 刚性。该项目将证明GPER通过一种新的分子保护脉管系统 非原位雌激素信号传导降低ROS并减轻糖胺聚糖的机制 （插科打）在细胞外基质中，从而保留中央动脉的机械性能和 降低脉搏波速度。此外，衰老引起的血管GPER表达降低会促进 对雌激素的不良反应，但可以用靶向该受体的选择性治疗剂纠正。 我们建议血管GPER可防止动脉僵硬，靶向这种受体将 改善对绝经后激素治疗的反应。结合体内，离体和 体外方法将使我们能够以多种方式评估我们的假设。高频超声将允许 脉冲波速度的体内测量，是评估血管刚度的金标准。而不是 传统的单轴压力矩形，双轴机械表型与与 生物医学工程师将允许使用计算模型来描述动脉的因素 刚性。 ROS测量将使用电子自旋共振光谱，直接和 量化生物样品中自由基的敏感方法。此外，诱导的，特异性的 GPER敲除鼠标模型将使我们能够专门评估减少血管GPER的影响 成年后对非选择性雌激素治疗的反应。