Hemodynamic Forces Affect Endothelial Cell Pheotype in Arterial Disease

血流动力学影响动脉疾病中的内皮细胞表型

• 批准号: 7610927
• 负责人: JOHN M TARBELL
• 金额: $ 37.61万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-10 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610927
• 关键词: Affect; Antibodies; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Biological; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cells; Characteristics; Common carotid artery; Computer Simulation; Conjugated Linoleic Acids; Coronary; Coronary artery; Development; Disease; Employee Strikes; Endothelial Cells; Endothelin-1; Environment; Event; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic Transcription; In Vitro; Influentials; Lead; Liquid substance; Literature; Mechanics; Mediating; Modeling; Molecular Profiling; Northern Blotting; Nuclear; Nutraceutical; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Phospho-Specific Antibodies; Proteins; Public Health; RNA Polymerase Inhibitor; Research; Role; Running; Signal Transduction; Solid; Stress; Surface; Testing; Thoracic aorta; Time; Tube; Western Blotting; atherogenesis; carotid sinus; computer studies; design; femoral artery; hemodynamics; in vivo; mRNA Stability; protein expression; research study; response; shear stress; src-Family Kinases

DESCRIPTION (provided by applicant): The fluid wall shear stress (WSS) driven by blood flow and the solid circumferential strain (CS) and associated circumferential stress driven by blood pressure act simultaneously on endothelial cells (ECs) lining blood vessels to modulate their phenotype. In recent dynamic computer simulations we showed that CS and WSS are most asynchronous (out-of-phase temporally) in precisely those regions of the circulation where atherosclerotic disease is most prominent (e.g., coronary arteries, carotid sinus). Our recent in vitro experiments have revealed a striking gene expression profile that is pro-atherogenic when CS and WSS are imposed asynchronously. We have observed a similar gene expression profile in the coronary arteries of rabbits. However, most studies of hemodynamic forces and atherogenesis have suggested that certain characteristics of WSS by itself induce an atherogenic phenotype without reference to CS or the interaction of CS and WSS. In the proposed research we will pursue the following studies in order to demonstrate the crucial role of the combined forces of CS and WSS and their phasic relationship in generating an atherogenic phenotype in endothelial cells in discrete regions of the circulation: 1. ECs grown on the inner surfaces of elastic tubes will be exposed to combined CS and WSS either synchronously or asynchronously, with a mean WSS that is either high or low. Gene expression profiles (48 genes) and EC turnover rates will be compared. The hypothesis is that asynchrony of forces will dominate mean WSS level in controlling EC phenotype. 2. The detailed biomolecular mechanism by which the eNOS gene is regulated when WSS and CS are applied synchronously or asynchronously will be determined as a first step toward understanding how these forces conspire to control EC phenotype. 3. The gene expression profiles (48 genes) of rabbit coronary arteries and carotid bifurcations (atherogenic) and common carotid arteries and femoral arteries (non-atherogenic) will be compared. The nutraceutical, conjugated linoleic acid (CLA), that was able to normalize atherogenic gene expression profiles in vitro, will be tested in the rabbit model to determine whether it can similarly alter EC phenotype in vivo. Project Narrative: The research is important to public health because it will determine which fundamental aspect of the mechanical environment of endothelial cells predisposes certain vessels (e.g., coronary arteries) to cardiovascular disease. In addition, the research will consider for the first time the possibility that pharmaceutical agents may normalize the pro-atherogenic endothelial phenotype induced by the mechanical environment inherent in the design of the cardiovascular system. This could ultimately lead to new drugs for the treatment of cardiovascular disease.

描述（由申请人提供）：由血流驱动的流体壁剪切应力（WSS）和由血压驱动的固体周向应变（CS）和相关周向应力同时作用于血管内皮细胞（EC）以调节其表型。在最近的动态计算机模拟中，我们表明，在动脉粥样硬化疾病最突出的循环区域（例如冠状动脉、颈动脉窦），CS 和 WSS 最为异步（时间上异相）。我们最近的体外实验揭示了一种引人注目的基因表达谱，当异步施加 CS 和 WSS 时，该基因表达谱会导致动脉粥样硬化。我们在兔子的冠状动脉中观察到类似的基因表达谱。然而，大多数关于血流动力学和动脉粥样硬化形成的研究表明，WSS 本身的某些特征会诱导动脉粥样硬化表型，而不涉及 CS 或 CS 与 WSS 的相互作用。在拟议的研究中，我们将进行以下研究，以证明 CS 和 WSS 的联合作用及其相位关系在循环离散区域内皮细胞中产生动脉粥样硬化表型中的关键作用： 1. 生长在弹性管内表面上的 EC 将同步或异步暴露于 CS 和 WSS 的组合中，平均 WSS 为 要么高要么低。将比较基因表达谱（48 个基因）和 EC 周转率。假设在控制 EC 表型时，力的异步性将主导平均 WSS 水平。 2. 同步或异步应用 WSS 和 CS 时调节 eNOS 基因的详细生物分子机制将被确定，作为了解这些力量如何共同控制 EC 表型的第一步。 3.比较兔冠状动脉和颈动脉分叉（致动脉粥样硬化）和颈总动脉和股动脉（非致动脉粥样硬化）的基因表达谱（48个基因）。营养保健品共轭亚油酸 (CLA) 能够在体外使致动脉粥样硬化基因表达谱正常化，将在兔子模型中进行测试，以确定它是否可以在体内类似地改变 EC 表型。 项目叙述：这项研究对公共卫生很重要，因为它将确定内皮细胞机械环境的哪个基本方面使某些血管（例如冠状动脉）容易患心血管疾病。此外，该研究将首次考虑药物可能使心血管系统设计中固有的机械环境诱导的促动脉粥样硬化内皮表型正常化的可能性。这最终可能导致治疗心血管疾病的新药的出现。