EFFECTS OF MODULATION OF PRESSURE AND FLOW ON VESSEL WALL ADAPTATION

拟议研究的目的是确定和联系 机制，在体内在合适的实验模型中，其a）调节 动脉对流量和压力变化的适应，B）确定 在高胆固醇血症条件下定位斑块，和c） 解释了高胆固醇血症、斑块形成 以及对改变的壁面剪应力和拉应力的适应机制。 我们 先前已经描述了壁面剪应力与壁面剪切应力之间的密切关系 和斑块定位，并建立了一个实验模型， 易损伤区和抗损伤区。 我们已经描述了 血管壁剪应力、张应力与动脉壁的关系 基础设施演进 这些发现揭示了动脉壁的适应性 改变流量和压力，斑块定位和代偿 动脉和斑块的扩大和建模是密切相关的 现象。 拟议的调查将在 结构、细胞和分子水平，利用设计的兔模型， 增加流量（动静脉瘘），减少流量（颈动脉流出 结扎），改变压力并建立易损伤和抗损伤 区域（主动脉缩窄）。 我们的方法包括超微结构， 动脉壁成分的形态测定和化学测定 （弹性蛋白、胶原蛋白（I型、III型、IV型和它们各自的蛋白酶），和 细胞增殖和肥大的定量。 表征 这些特征的基因表达，包括原位杂交， 希望澄清的序列和空间定位的 引起高胆固醇血症的存在和不存在的变化， 斑块形成 一个基本特征是空间相关性， 我们的研究结果与相应的定量流场定位 项目0031中的特征和相关的生物力学-细胞 在0034项目中发现的相互作用。 我们的研究应该提供新的 深入了解血管壁适应改变的性质和限制， 机械条件和斑块的形成。

The objective of the proposed research is to identify and relate the mechanisms, in vivo in suitable experimental models, which a) regulate the adaptation of arteries to changes in flow and pressure, b) determine the localization of plaques under conditions of hypercholesterolemia, and c) account for the interactions among hypercholesterolemia, plaque formation and the adaptive mechanisms to altered wall shear and tensile stresses. We have previously described a close relationship between wall shear stress and plaque localization, and developed an experimental model of lesion prone and lesion resistant regions. We have characterized the quantitative relationships among wall shear stress, tensile stress and artery wall infrastructure. These findings have revealed that artery wall adaptation to altered flow and pressure, plaque localization and the compensatory enlargement and modelling of arteries and plaques are a closely related phenomena. The proposed investigations will be carried out at the structural, cellular and molecular level, utilizing rabbit models designed to increase flow (arterio-venous fistula), decrease flow (carotid outflow ligation), alter pressure and establish lesion prone and lesion resistant regions (aortic coarctation). Our methods include ultrastructural, morphometric and chemical determinations of artery wall composition (elastin, collagen (Types I, III, IV and their respective proteases), and quantitation of cell proliferation and hypertrophy. Characterization of gene expression for these features, including in situ hybridization is expected to clarify both the sequence and spatial localization of the elicited changes in the absence and presence of hypercholesterolemia and plaque formation. An essential feature will be the correlation of spatial localization of our findings with the corresponding quantitative flow field characterizations in Project 0031 and the related biomechanical-cellular interactions revealed in Project 0034. Our research should provide new insights into the nature and limits of vessel wall adaptation to altered mechanical conditions and to the formation of plaques.