Hemodynamic Forces Affect Endothelial Cell Pheotype in Arterial Disease

描述（由申请人提供）：血流驱动的流体壁剪切应力（WSS）和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衬的内皮细胞（EC），以调节其表型。在最近的动态计算机模拟中，我们表明CS和WSS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）。我们最近的体外实验揭示了一个惊人的基因表达谱，是促动脉粥样硬化时，CS和WSS是异步施加。我们在兔子的冠状动脉中观察到了类似的基因表达谱。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本身的某些特征诱导了致动脉粥样硬化表型，而不涉及CS或CS和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的内皮细胞中产生致动脉粥样硬化表型的阶段性关系的关键作用：1.在弹性管的内表面上生长的EC将同步或异步地暴露于组合CS和WSS，其中平均WSS为高或低。将比较基因表达谱（48个基因）和EC周转率。这一假设是，在控制EC表型时，力的作用将主导平均WSS水平。2.详细的生物分子机制，其中eNOS基因的调节时，WSS和CS同步或异步应用将被确定为了解这些力量如何合谋控制EC表型的第一步。3.将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）的基因表达谱（48个基因）。将在兔模型中测试能够使体外致动脉粥样硬化基因表达谱正常化的营养品共轭亚油酸（CLA），以确定其是否可以类似地改变体内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的机械环境的哪个基本方面使某些血管（例如，冠状动脉）到心血管疾病。此外，该研究将首次考虑药物制剂可能使由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。这可能最终导致治疗心血管疾病的新药。

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.