Vessel Stiffening, Hypertension and Vascular Extracellular Matrix

描述（由申请人提供）：大动脉作为心脏喷射血液的弹性储存库。它们在收缩期扩张，在舒张期放松，将血液推向远端血管，抑制压力脉搏波。这种“风管”功能还可以减少左心室后负荷，改善冠状动脉血流和左室舒张。在疾病和衰老中，动脉顺应性降低，这损害了动脉的风管功能，增加了死于心脏病的风险。最近的证据表明，仅仅是升主动脉顺应性的局部下降，而不是动脉顺应性的整体下降，可能会对心功能产生不利影响。主动脉顺应性取决于施加的血压、血管壁的几何形状和材料特性。被动材料的性能主要取决于细胞外基质（ECM）蛋白的数量和组织，包括弹性蛋白和胶原蛋白。量化主动脉材料特性的一种有效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，这种弹性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，维持恒定弹性模量的需要指导了升主动脉的构建，以最大限度地减少左室后负荷和心脏所做的工作。我们认为，平滑肌细胞（SMCs）通过定向生长和增殖，以及适当数量、位置和组织的ECM蛋白的产生来协调这一过程，从而形成具有特定材料特性的主动脉壁，并且这一过程是通过TGF-ß活性调节的。我们假设结合血流动力学力、力学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。我们将使用新的小鼠模型来测试我们的假设，其中弹性蛋白的数量和时间可以调节。通过了解SMCs如何形成并维持具有普遍弹性模量的主动脉壁，以及在无法维持弹性模量的极端条件下，我们可以获得治疗与主动脉顺应性降低相关的心血管疾病的有用信息。这些疾病包括基因缺陷，这些遗传缺陷特异性地改变了用于壁构建的可用ECM蛋白（如瓣上主动脉狭窄、马凡氏综合征和血管扭曲综合征），以及与顺应性降低相关的疾病，如主动脉缩窄和收缩期高血压。我们的具体目的是：1)确定维持通用弹性模量的需求如何通过调节TGF-ß活性来指导主动脉壁生长；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弹性模量；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。

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.