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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.

摘要