Vessel Stiffening, Hypertension and Vascular Extracellular Matrix

描述（由申请人提供）：大动脉的功能是作为心脏喷射血液的弹性储存器。它们在收缩期扩张，在舒张期放松，将血液推到远端血管，抑制压力脉搏波。这种“windkessel”功能也减少了左心室（LV）后负荷，改善了冠状动脉血流和LV舒张。在疾病和衰老中，动脉顺应性降低，这损害了动脉的Windkessel功能并增加了死于心脏病的风险。最近的证据表明，升主动脉顺应性的局部降低，而不是动脉顺应性的整体降低，可能会对心脏功能造成不良影响。主动脉顺应性取决于所施加的血压、壁的几何形状和材料特性。被动材料的性质主要由细胞外基质（ECM）蛋白（包括弹性蛋白和胶原蛋白）的数量和组织决定。量化主动脉材料特性的一种有用方法是计算生理压力下周向拉伸-应力曲线的斜率或模量。实验证据表明，该模量在不同的发育年龄、人类疾病的小鼠模型和生物体中是恒定的，这表明“通用弹性模量”是一种生理设计约束。我们假设，需要保持恒定的弹性模量指导升主动脉的建设，以尽量减少左心室后负荷和心脏所做的工作。我们提出，平滑肌细胞（SMC）通过定向生长和增殖，以及ECM蛋白在正确的数量、位置和组织中的产生来协调这一过程，以产生具有特定材料特性的主动脉壁，并且这一过程通过TGF-β活性来调节。我们假设，数学模型结合血液动力学的力量，机械行为，和生理常数，可以用来更好地理解和预测这种增长和重塑过程。我们将测试我们的假设，使用新的小鼠模型，其中弹性蛋白的数量和时间可以调制。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，我们可以获得在治疗与主动脉顺应性降低相关的心血管疾病时有用的信息。这些疾病包括特异性改变用于壁构造的可用ECM蛋白的遗传缺陷（即，瓣上主动脉狭窄、马凡氏综合征和血管迂曲综合征），以及与顺应性的一般降低相关的遗传缺陷，如主动脉缩窄和收缩期高血压。我们的具体目标是：1）确定维持通用弹性模量的需要如何通过调节TGF-β活性来引导主动脉壁生长; 2）量化弹性蛋白和胶原蛋白的量和组织如何相互作用以维持通用弹性模量; 3）将机械和生理数据整合到主动脉生长和重塑的数学模型中。

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.