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: 9223725
• 负责人: ROBERT P. MECHAM
• 金额: $ 49.56万
• 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/9223725
• 关键词: Adverse effects; Age; Aging; Animal Model; Aorta; Aortic coarctation; Arteries; Blood; Blood Pressure; Blood Vessels; Blood flow; Cardiac; Cardiovascular Diseases; Cell Proliferation; Cessation of life; Collagen; Collagen Fiber; Complex; Coronary; Data; Development; Diastole; Disease; Distal; Elastic Fiber; Elastin; Elastin Fiber; Elderly; Extracellular Matrix; Extracellular Matrix Proteins; Geometry; Growth; Heart; Heart Diseases; Hypertension; Individual; Investigation; Lead; Left; Location; Marfan Syndrome; Measures; Mechanics; Modulus; Mus; Mutation; Organism; Pathologic; 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; mechanical properties; middle age; mouse model; novel; postnatal; pressure; prevent; public health relevance; 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(申请人提供)：大动脉的功能是心脏排出的血液的弹性储存库。它们在收缩时扩张，在舒张期放松，将血液推向远端血管，抑制压力脉搏波。这种“风起搏”功能还可以减少左心室后负荷，改善冠脉血流量和左心室松弛。在疾病和衰老中，动脉顺应性降低，这损害了动脉的风团功能，增加了死于心脏病的风险。最近的证据表明，仅是升主动脉局部顺应性的下降，而不是动脉顺应性的整体下降，可能会对心功能造成不利影响。主动脉顺应性取决于施加的血压、几何形状和壁的材料特性。被动材料的性能主要由细胞外基质(ECM)蛋白的数量和组织决定，包括弹性蛋白和胶原。量化主动脉材料特性的一种有效方法是计算生理压力下的周向拉伸-应力曲线的斜率或模数。实验证据表明，这个模数在不同发育年龄、人类疾病的小鼠模型和生物体中都是恒定的，这表明“通用弹性模数”是一种生理设计约束。我们假设，保持恒定弹性模数的需要指导升主动脉的构建，以最小化LV后负荷和心脏所做的功。我们认为，平滑肌细胞(SMCs)通过定向生长和增殖，并在适当的数量、位置和组织中产生ECM蛋白来协调这一过程，以创建具有特定材料特性的主动脉壁，并且这一过程通过转化生长因子-β活性来调节。我们假设，包含血流动力、机械行为和生理常数的数学模型可以用来更好地理解和预测这种生长和重塑过程。我们将使用可以调节弹性蛋白数量和时间的新型小鼠模型来验证我们的假设。通过了解SMC如何创造和维持具有通用弹性模数的主动脉壁，以及在极端情况下无法维持该模数，我们可以获得有助于治疗与主动脉顺应性降低相关的心血管疾病的信息。这些疾病包括专门改变可用于室壁构建的ECM蛋白的基因缺陷(即瓣膜上主动脉狭窄、马凡综合征和血管扭曲综合征)，以及与顺应性普遍下降有关的疾病，如主动脉缩窄和收缩压增高。我们的具体目标是：1)确定维持通用弹性模数的需要如何通过调节转化生长因子的活性来指导主动脉壁的生长；2)量化弹性蛋白和胶原的数量和组织如何相互作用以维持通用弹性模数；3)将力学和生理数据整合到主动脉生长和重塑的数学模型中。