VESSEL STIFFENING, HYPERTENSION, AND VASCULAR EXTRACELLULAR MATRIX

摘要 老化的一个重要后果是大弹性动脉的顺应性降低（硬化）， 这损害了它们的能量存储和脉冲阻尼功能， 不良心血管事件。在发育和成熟过程中， 细胞外基质（ECM）蛋白，弹性蛋白和胶原蛋白，受到调节，使主动脉维持 由生理弹性模量定义的适当的机械性能。增加弹性 弹性模量和因此降低动脉顺应性与年龄表明，生产弹性蛋白， 胶原蛋白变得不同步，导致胶原蛋白的积累远远超过 弹性蛋白这种疤痕样的ECM导致血压升高，因为心脏泵送的血液中含有较少的 顺应性管，动脉壁应力增加，负反馈中胶原沉积更多 周期在此修订申请中，我们要求资金扩大我们的母公司R 01的研究， 在主动脉发育过程中控制ECM的产生，包括老化。我们特别希望 探索弹性蛋白和胶原蛋白积累和组织解偶联背后的机制 以及TGFβ信号是否在衰老过程中发生变化。为了实现我们的目标，我们将使用新颖的鼠标 在这些模型中，弹性蛋白的量以及因此的主动脉顺应性可以被调节。这些模型将 与野生型小鼠的正常衰老过程进行比较， 当适当的生理弹性模量 无法实现。我们还将继续开发数学模型， 血流动力学力、主动脉壁结构和机械行为，以更好地理解和预测 衰老的重塑过程我们的具体目标是：1）识别差异化的途径， 在适应性、正常和病理性中调节ECM产生和平滑肌细胞增殖， 主动脉老化; 2）量化弹性蛋白和胶原蛋白的数量和组织重塑如何影响主动脉的老化。 老化中的主动脉模量;以及3）将机械和生理数据整合到数学模型中。 模型，以更好地了解和预测老化中的主动脉重塑。

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.