Vessel Stiffening, Hypertension and Vascular Extracellular Matrix

血管硬化、高血压和血管细胞外基质

• 批准号: 8886630
• 负责人: ROBERT P. MECHAM
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886630
• 关键词: Adverse effects; Age; Aging; Animal Model; Aorta; Arteries; Blood; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cell Proliferation; Cessation of life; Coarctation of the aorta; Collagen; Collagen Fiber; Complex; Coronary; Data; Development; Diastole; Disease; Distal; Elastic Fiber; Elastin; Elastin Fiber; Elderly; Extracellular Matrix; Extracellular Matrix Proteins; Geometry; Growth; Health; Heart; Heart Diseases; Hypertension; Individual; Investigation; Lead; Left; Location; Marfan Syndrome; Measures; Mechanics; Mus; Mutation; Organism; Pathology; Physiological; Process; Production; Property; Protein Deficiency; Proteins; Pulse Pressure; Regulation; Relaxation; Risk; Smooth Muscle Myocytes; Stress; Stretching; Supravalvular aortic stenosis; Syndrome; Systole; Testing; Time; Transforming Growth Factor beta; Ventricular; Work; arterial stiffness; ascending aorta; design; heart function; hemodynamics; human disease; improved; mathematical model; mechanical behavior; middle age; mouse model; novel; postnatal; pressure; prevent; pulse pressure wave; systolic hypertension

DESCRIPTION (provided by applicant): The large arteries function as elastic reservoirs for blood ejected by the heart. They distend during systole and relax during diastole, pushing blood to distal vessels and dampening the pressure pulse wave. This "windkessel" function also reduces left ventricular (LV) afterload and improves coronary blood flow and LV relaxation. In disease and aging, arterial compliance is reduced, which compromises the arterial windkessel function and increases the risk of death from heart disease. Recent evidence suggests that local decreases in compliance of the ascending aorta alone, rather than global decreases in arterial compliance, can cause adverse effects on cardiac function. The aortic compliance depends on the applied blood pressure, geometry, and material properties of the wall. The passive material properties are determined mostly by the amount and organization of extracellular matrix (ECM) proteins, including elastin and collagen. One way useful way to quantify the aortic material properties is to calculate the slope, or modulus, of the circumferential stretch-stress curve at physiologic pressure. Experimental evidence shows that this modulus is constant across different developmental ages, mouse models of human disease, and organisms, suggesting a "universal elastic modulus" that is a physiological design constraint. We hypothesize that the need to maintain a constant elastic modulus directs the construction of the ascending aorta to minimize LV afterload and the work done by the heart. We propose that smooth muscle cells (SMCs) orchestrate this process by directed growth and proliferation, and production of ECM proteins in the right amount, location, and organization to create an aortic wall with specific material properties and that this process is regulated through TGF-ß activity. We postulate that mathematical models incorporating hemodynamic forces, mechanical behavior, and physiological constants, can be used to better understand and predict this growth and remodeling process. We will test our hypothesis using novel mouse models in which elastin amounts and timing can be modulated. By understanding how SMCs create and maintain the aortic wall with a universal elastic modulus, and the extreme conditions in which the modulus cannot be maintained, we can gain information that will be useful in treating cardiovascular diseases related to decrease aortic compliance. These diseases include genetic defects that specifically alter the available ECM proteins for wall construction (i.e. supravalvular aortic stenosis, Marfan Syndrome, and vascular tortuosity syndromes), as well as those related to general decreases in compliance, such as coarctation of the aorta and systolic hypertension. Our specific aims are to: 1) Determine how the need to maintain a universal elastic modulus directs aortic wall growth through regulation of TGF-ß activity; 2) Quantify how elastin and collagen amounts and organization interact to maintain a universal elastic modulus; 3) Integrate mechanical and physiological data into a mathematical model of aortic growth and remodeling.

描述（由适用提供）：大动脉作为心脏弹出的血液的弹性储量。它们在收缩期间扩张，并在舒张期间放松，将血液推向远端vissels，并使压力脉冲波诅咒。此“ Windkessel”功能还减少了左心室（LV）后负荷，并改善了冠状动脉流动和LV松弛。在疾病和衰老中，动脉依从性降低了，这会损害Windkessel功能，并增加心脏病死亡的风险。最近的证据表明，局部依从性主动脉的依从性下降，而不是艺术依从性的全球性下降，可能会对心脏功能产生不利影响。主动脉依从性取决于壁的施加的血压，几何形状和材料特性。被动物质特性主要取决于包括弹性蛋白和胶原蛋白在内的细胞外基质（ECM）蛋白的数量和组织。量化主动脉材料特性的一种有用方法是计算生理压力下圆周拉伸压力曲线的斜率或模量。实验证据表明，这种模量在不​​同的发育年龄，人类疾病的小鼠模型和生物体中都是恒定的，这表明是物理设计约束的“通用弹性模量”。我们假设维持恒定的弹性模量的需求指导升主动脉的构建，以最大程度地减少LV后负载和心脏完成的工作。我们建议平滑肌细胞（SMC）通过定向生长和增殖以及在适当数量，位置和组织中生产ECM蛋白来制作该过程，以创建具有特定材料特性的主动脉壁，并且该过程通过TGF-ß活动调节。我们假设数学模型结合了血液动力学，机械行为和生理常数，可用于更好地理解和预测这种生长和重塑过程。我们将使用新型的小鼠模型来检验我们的假设，其中弹性蛋白量和时间可以调节。通过了解SMC如何创建和维持具有通用弹性模量的主动脉壁，以及无法维持模量的极端条件，我们可以获得对治疗与降低主动脉依赖性相关的心血管疾病有用的信息。这些疾病包括特异性改变可用的ECM蛋白的遗传缺陷（即，上主动脉狭窄，Marfan综合征和血管折磨综合征），以及与一般依从性相关的遗传缺陷，例如主动脉和主动脉和感染性高血压的一般下降。我们的具体目的是：1）确定如何维持通用弹性模量的需求通过调节TGF-β活性来指导主动脉壁的生长； 2）量化弹性蛋白和胶原蛋白的数量和组织如何相互作用以维持通用的弹性模量； 3）将机械和物理数据整合到主动脉生长和重塑的数学模型中。