DYNAMICS OF FLOW-DEPENDENT ARTERIAL PERMEABILITY

血流相关的动脉渗透性的动力学

• 批准号: 6389288
• 负责人: MORTON H FRIEDMAN
• 金额: $ 34.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389288
• 关键词: albumins; artery; atherosclerotic plaque; cell adhesion; cellular respiration; computer simulation; densitometry; hemodynamics; hypercholesterolemia; mathematical model; swine; tissue /cell culture; tissue /cell preparation; vascular endothelium permeability; vascular resistance

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.

本研究的总体目标是了解影响大分子跨内皮进入动脉壁的因素，特别是局部血流动力学对该过程的调节。大分子转运在动脉粥样硬化发生和发展中的重要性引起了人们对大分子转运的兴趣。血流动力学因素对动脉摄取的调节特别令人感兴趣，因为动脉粥样硬化病变的分布表明血流动力学因素可能与疾病的定位有关。此外，有证据表明血流动力学应激可以影响内皮通透性。这项研究的一个主要假设是，跨内皮通量的重要部分发生在流量变化引起的渗透性增加期间。因此，特别强调内皮屏障功能对血流动力学环境变化的动态响应。研究目标是通过动物实验、计算机模拟以及细胞和分子生物学的独特组合来实现的。猪髂总动脉中白蛋白渗透性的空间变化，无论是在基线还是在改变血流的干预措施之后，都将使用伊文思蓝染料的照相密度测定法来测量白蛋白的摄取。流量的改变将由可逆、可调节的股动脉动静脉分流器产生。髂血管中壁剪切应力的分布以及因操纵分流器引起的应力变化将通过动脉和近端脉管系统注射铸件区域中经过验证的流体动力学计算获得；将评估和建模白蛋白摄取对血流动力学压力和压力变化的依赖性。在一组单独的动物中，不会注射铸型材料，并且来自感兴趣区域的组织将被固定或外植并培养，并且将使用多种技术将渗透性的变化与细胞特性联系起来。特别令人感兴趣的是介导细胞氧化还原状态、细胞骨架的完整性、其与邻近细胞的连接以及与基质的粘附的特性。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导致流量变化对血管摄取的影响。