DYNAMICS OF FLOW-DEPENDENT ARTERIAL PERMEABILITY

本研究的总体目标是了解影响大分子经内皮进入动脉壁的因素，特别是局部血流动力学对这一过程的介导。大分子转运在关节炎发生发展中的重要性促使人们对大分子转运的兴趣。动脉摄取的血液动力学因素的调解是特别感兴趣的，因为动脉粥样硬化病变的分布表明，血液动力学因素可能参与疾病的定位;此外，有证据表明，血液动力学应激可以影响内皮渗透性。本研究的一个主要假设是，一个重要部分的transendothelial流量发生在渗透性增加的流量变化提示，因此，特别强调的是放在动态响应的内皮细胞衬里的屏障功能的血流动力学环境的变化。研究目标通过动物实验，计算机模拟和细胞与分子生物学的独特组合来实现。将使用伊文思蓝染料的光密度测定法测量白蛋白摄取，获得基线时或改变血流的干预后猪髂外动脉中白蛋白渗透性的空间变化。血流的改变将由可逆的、可调节的股动静脉分流术产生。将通过动脉和近端血管注射模型衍生区域的经验证流体动力学计算获得壁面剪切应力分布和操作分流管引起的应力变化;将评估和建模白蛋白摄取对血流动力学应力的依赖性和应力变化。在一组单独的动物中，将不注射铸造材料，并且将来自感兴趣区域的组织固定或固定并培养，并且将使用各种技术将渗透性的变化与细胞特性联系起来。特别感兴趣的是介导细胞的氧化还原状态、细胞骨架的完整性及其与邻近细胞的连接和与基质的粘附的性质。还将检查高胆固醇血症对血管通透性的影响及其对流量变化的动态响应，以确定高脂质水平是否可能影响流量变化对血管摄取的影响。

The overall objective of this research is to understand the factors affecting the transendothelial entry of macromolecules into the arterial wall, and particularly the mediation of this process by local hemodynamics. The interest in macromolecular transport is prompted by its importance in the genesis and development of artherosclerosis. The mediation of arterial uptake by hemodynamic factors is of particular interest because the distribution of atherosclerotic lesions suggests that hemodynamic factors may be involved in the localization of the disease; furthermore, there is evidence that hemodynamic stress can influence endothelial permeability. A primary hypothesis of this research is that an important fraction of the transendothelial flux occurs during increases in permeability prompted by changes in flow; accordingly, particular emphasis is placed on the dynamic response of the barrier function of the endothelial lining to changes in the hemodynamic environment. The research objectives are addressed through a unique combination of animal experiments, computer simulation and cell and molecular biology. The spatial variation of the albumin permeability in the eternal iliac arteries of swine, either at baseline or subsequent to interventions that alter flow, will be obtained using photographic densitometry of Evans Blue dye to measure albumin uptake. The alterations in flow will be produced by reversible, adjustable femoral arteriovenous shunts. The distribution of wall shear stress, and of the changes in stress caused by manipulating the shunt, in the iliac vessels will be obtained from validated fluid dynamic computations in regions derived from injection casts of the arteries and the proximal vasculature; the dependence of albumin uptake on hemodynamic stress, and alterations in stress, will be assessed and modeled. In a separate set of animals, casting material will not be injected, and tissue from the region of interested will be fixed or explanted and cultured, and a variety of techniques will be used to relate the variations in permeability to cellular properties. Of particular interest are properties that mediate the redox state of the cell, the integrity of the cytoskeleton, and its junctions with neighboring cells and adhesion to the substratum. The effects of hypercholesterolemia on vascular permeability and its dynamic response to changes in flow will be examined as well, to determine whether high lipid levels potential the effects of flow changes on vascular uptake.