Hemodynamic Forces Affect Endothelial Cell Pheotype in Arterial 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）以及相关的周向应力同时作用于血管内膜内皮细胞（ECs）以调节其表型。在最近的动态计算机模拟中，我们发现CS和WSS在动脉粥样硬化疾病最突出的循环区域（如冠状动脉、颈动脉窦）是最不同步的（暂时的非相位）。我们最近的体外实验显示，当CS和WSS不同步施加时，显著的基因表达谱会促进动脉粥样硬化。我们在家兔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力和动脉粥样硬化的研究表明，WSS的某些特征本身诱导了动脉粥样硬化表型，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的联合力量及其在循环离散区域内皮细胞中产生动脉粥样硬化表型的相位关系的关键作用：生长在弹性管内表面的ECs将同时或不同步地暴露于CS和WSS组合中，平均WSS可高可低。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，非同步力将主导平均WSS水平。2. 当WSS和CS同步或不同步应用时，eNOS基因调控的详细生物分子机制将被确定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）以及颈总动脉和股动脉（非致动脉粥样硬化）的48个基因表达谱。在体外能够使动脉粥样硬化基因表达谱正常化的营养保健品共轭亚油酸（CLA）将在兔模型中进行测试，以确定它是否能在体内类似地改变EC表型。

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.