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）中的作用在确定心血管疾病（CVD）中的作用仍然是一个严重不足的研究领域。 病因、病理学和有效的治疗方法。而男性的 CVD 风险逐渐增加 在整个生命周期中，绝经前妇女可以免受心血管疾病相关疾病的影响。然而，绝经后 女性心血管疾病的发病率急剧增加。内皮细胞功能障碍可能导致这些性行为 CVD 风险的激素依赖性差异。在这里，我们试图调查性和性激素的影响 - 继发于左心衰竭的 CVD 疾病进展的依赖性差异 (PH-LHF)。 目标 1：研究性和性激素在肺内皮细胞力转导中的作用 和疾病进展。首先，我们将检验女性性别改变内皮细胞信号传导的假设 对机械剪切应力的响应。人类男性和女性肺动脉、静脉和微血管 内皮细胞将受到生理、高和低水平的剪切应力 (σ) 的影响，以测量 性别与性激素无关。其次，研究性与女性性激素的作用， 雄性和雌性细胞都将以生理或病理σ剂量施用性激素。这些体外结果 使用已建立的方法将被确认为体内胶原蛋白过度产生和慢性血管收缩的驱动因素 PH-LHF小鼠模型。 目标 2：确定性和性激素在 PH-LHF 进展中的作用以及耦合 PH-LHF 的肺血流动力学和内皮细胞动力学模型。据了解，现有 文献中，我们将开发内皮细胞对改变的 σ、性别和性别的反应的化学动力学模型 荷尔蒙。使用理想化的人体结构和血液动力学数据，我们将开发一个计算模型 肺血管系统与关键信号因子的化学动力学方程相结合。范围 值和依赖性将根据目标 1 中收集的体外数据进行验证。以确认预测 能力，该模型将根据 PH-LHF 的体内小鼠模型进行校准，并用于估计肺 动脉和静脉重塑。