VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

血管硬化、高血压和血管细胞外基质

基本信息

批准号：
9174403
负责人：
ROBERT P. MECHAM
金额：
$ 11.44万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174403
关键词：
Affect Age Aging Aging-Related Process Aorta Arteries Blood Pressure Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Proliferation Cicatrix Collagen Collagen Fiber Data Deposition Development Disease Elastic Fiber Elastin Elderly Event Extracellular Matrix Extracellular Matrix Proteins Feedback Funding Heart Heart Diseases Hypertension Individual Intervention Mechanics Modeling Mus Parents Pathology Pathway interactions Peptide Hydrolases Physiologic pulse Physiological Process Production Property Pulse Pressure Pump Request for Applications Risk Signal Transduction Smooth Muscle Myocytes Stress Structure Transforming Growth Factor beta Tube Wild Type Mouse Work abstracting age related arterial stiffness ascending aorta hemodynamics mathematical model mature animal mechanical behavior middle age mouse model normal aging novel pathological aging public health relevance research study

项目摘要

ABSTRACT A significant consequence of aging is reduced compliance (stiffening) of the large elastic arteries, which compromises their energy storage and pulse dampening function and increases the risk of adverse cardiovascular events. During development and maturation, production and deposition of the extracellular matrix (ECM) proteins, elastin and collagen, are regulated so that the aorta maintains appropriate mechanical properties defined by a physiological elastic modulus. Increased elastic modulus and consequently reduced arterial compliance with aging suggests that production of elastin and collagen becomes unsynchronized, resulting in collagen accumulation far exceeding that of elastin. This scar-like ECM results in elevated blood pressure as the heart pumps against a less compliant tube, increased arterial wall stress, and more collagen deposition in a negative feedback cycle. In this revision application we are requesting funds to expand the studies in our parent R01 on the control of ECM production during aortic development to include aging. We wish to specifically explore the mechanism behind the uncoupling of elastin and collagen accumulation and organization and whether TGFβ signaling changes during aging. To accomplish our aims, we will use novel mouse models in which elastin amounts and, hence, aortic compliance, can be modulated. These models will be compared to the normal aging process in wild-type mice so that we can identify mechanisms behind the aortic pathology that occurs with aging when the appropriate physiological elastic modulus cannot be achieved. We will also continue to develop mathematical models incorporating hemodynamic forces, aortic wall structure and mechanical behavior, to better understand and predict the remodeling process in aging. Our specific aims are to: 1) Identify pathways that differentially regulate ECM production and smooth muscle cell proliferation in adaptive, normal, and pathological aortic aging; 2) Quantify how elastin and collagen amounts and organization remodel to affect the aortic modulus in aging; and 3) Integrate mechanical and physiological data into a mathematical model to better understand and predict aortic remodeling in aging.

抽象的衰老的一个显着后果是大弹性动脉的顺应性降低（硬化），这会损害其能量存储和脉冲抑制功能，并增加风险不良心血管事件在发育和成熟、产生和沉积过程中。细胞外基质 (ECM) 蛋白、弹性蛋白和胶原蛋白受到调节，以便主动脉维持由生理弹性模量定义的适当的机械性能增加的弹性。随着年龄的增长，模量和动脉顺应性降低表明弹性蛋白的产生胶原蛋白变得不同步，导致胶原蛋白的积累远远超过当心脏泵血时，这种类似疤痕的 ECM 会导致血压升高。顺应性管、动脉壁应力增加以及负反馈中更多的胶原蛋白沉积在此修订申请中，我们请求资金来扩展我们母版 R01 中的研究。我们希望特别关注主动脉发育过程中 ECM 产生的控制，包括衰老。探索弹性蛋白和胶原蛋白积累和组织解偶联背后的机制以及 TGFβ 信号传导在衰老过程中是否会发生变化为了实现我们的目标，我们将使用新型小鼠。可以调节弹性蛋白量以及主动脉顺应性的模型这些模型将被调节。与野生型小鼠的正常衰老过程进行比较，以便我们能够确定机制当适当的生理弹性模量时，随着年龄的增长而发生的主动脉病变背后我们还将继续开发数学模型，将其纳入其中。血流动力学、主动脉壁结构和机械行为，以便更好地理解和预测我们的具体目标是：1）确定差异化的途径。在适应性、正常和病理状态下调节 ECM 产生和平滑肌细胞增殖主动脉老化；2) 量化弹性蛋白和胶原蛋白的含量以及组织重塑对主动脉衰老的影响衰老过程中的主动脉模量；3) 将机械和生理数据整合到数学模型中模型可以更好地理解和预测衰老过程中的主动脉重塑。