Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

性和性激素对左心衰竭继发肺动脉高压力学生物学机制的影响

• 批准号: 10598399
• 负责人: Naomi C Chesler
• 金额: $ 9.49万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598399
• 关键词: Adult; Animal Model; Area; Arteries; Biomechanics; Blood Vessels; Blood capillaries; Cardiac Output; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Collagen; Computer Models; Coupled; Data; Dependence; Diagnosis; Disease; Disease Progression; Dose; EFRAC; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Equation; Equilibrium; Etiology; Exposure to; Female; Functional disorder; Genetic; Goals; Gonadal Steroid Hormones; Heart Atrium; Heart failure; Homeostasis; Human; Impairment; In Vitro; Knowledge; Left; Literature; Longevity; Lung; Measures; Mechanics; Mediator of activation protein; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; NOS3 gene; Pathologic; Pathology; Patient-Focused Outcomes; Physiological; Postmenopause; Premenopause; Process; Production; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary artery structure; Pulmonary veins; Role; Secondary to; Sex Differences; Signal Transduction; Stimulus; Stretching; Structure; System; Testing; Text; Time; Veins; Venous; Woman; arterial stiffness; cardiovascular disorder risk; chemical kinetics; effective therapy; experience; female sex hormone; hemodynamics; human female; human male; improved outcome; in vivo; individual patient; kinetic model; male; mechanical stimulus; mechanotransduction; men; mortality; mouse model; multimodality; novel; novel therapeutics; porcine model; pressure; pulmonary arterial hypertension; pulmonary arterial pressure; pulmonary vascular remodeling; response; right ventricular failure; sex; shear stress; vasoconstriction

PROJECT ABSTRACT The role of sex in cardiovascular disease (CVD) remains a critically understudied area in determining the etiology, pathology, and effective treatments. Whereas men experience a gradual increase in CVD risk over the lifespan, premenopausal women are protected from CVD-related pathologies. However, post-menopause the onset of CVD in women increases dramatically. Endothelial cell dysfunction may contribute to these sex and sex hormone-dependent differences in CVD risk. Here we seek to investigate the impact of sex and sex hormone- dependent differences in progression of the CVD disease pulmonary hypertension secondary to left heart failure (PH-LHF). Aim 1: Investigate the role of sex and sex hormones in pulmonary endothelial cell mechanotransduction and disease progression. First, we will test the hypothesis that female sex alters endothelial cell signaling in response to mechanical shear stress. Human male and female pulmonary artery, vein, and microvascular endothelial cells will be exposed to physiologic, high, and low levels of shear stress (σ) to measure the effect of sex independent of sex hormones. Second, to investigate the role of sex coupled with female sex hormones, both male and female cells will be dosed with sex hormones at physiologic or pathologic σ. These in vitro results will be confirmed as drivers of collagen over-production and chronic vasoconstriction in vivo using the established mouse model of PH-LHF. Aim 2: Determine the role of sex and sex hormones in the progression of PH-LHF with a coupled pulmonary hemodynamics and endothelial cell kinetics model of PH-LHF. Informed by the existing literature, we will develop a chemical kinetics model of the endothelial response to altered σ, sex, and sex hormones. Using idealized human structural and hemodynamic data we will develop a computational model of the pulmonary vasculature integrated with the chemical kinetics equations for key signaling factors. Parameter values and dependencies will be validated against the in vitro data collected in Aim 1. To confirm predictive capability, the model will be calibrated to the in vivo mouse model of PH-LHF and used to estimated pulmonary artery and vein remodeling.

项目摘要 性别在心血管疾病（CVD）中的作用仍然是一个备受瞩目的领域。 病因，病理学和有效治疗。而男人的CVD风险比 寿命，绝经前妇女受到与CVD相关的病理的保护。但是，生气后 女性CVD的发作急剧增加。内皮细胞功能障碍可能会导致这些性别和性别 CVD风险依赖马酮的差异。在这里，我们试图调查性和性爱的影响 - CVD疾病肺动脉高压的依赖性差异 （ph-lhf）。 AIM 1：研究性别和性激素在肺部内皮细胞机械转导中的作用 和疾病进展。首先，我们将检验以下假设：女性性别会改变内皮细胞信号传导 对机械剪切应力的反应。人类和雌性肺动脉，静脉和微血管 内皮细胞将暴露于生理，高和低水平的剪应力（σ），以测量 性独立于性骑马。其次，为了调查性别的作用以及女性性骑马的作用， 在生理或病理σ上，男性和雌性细胞都将用性激素涂抹。这些体外结果 使用已建立 pH-LHF的小鼠模型。 目标2：确定性别和性激素在pH-LHF进展中的作用 pH-LHF的肺血液动力学和内皮细胞动力学模型。被现有的信息 文献，我们将开发一种对改变σ，性别和性别的内皮反应的化学动力学模型 使用理想化的人类结构和血液动力学数据，我们将开发一个计算模型 肺脉管系统与关键信号因子的化学动力学方程整合在一起。范围 值和依赖项将在AIM 1中收集的体外数据进行验证。确认预测性 能力，该模型将被校准到pH-LHF的体内小鼠模型，并用于估计肺部 动脉和静脉重塑。