The interplay between hemodynamic forces and inflammatory processes in the development and destabilization of atherosclerotic plaque

动脉粥样硬化斑块的形成是局部血流模式和炎症过程共同作用的结果。本项目重点关注血流动力学力与炎症激动剂联合对动脉粥样硬化病变发生、进展和不稳定的影响，以及这些过程的药理调节的治疗可能性。1. 利用分叉流式细胞培养载片，我们将把内皮细胞暴露在动脉水平的层流或非均匀剪切应力下，以分析重要的内皮功能，例如在特定的血流条件下，在存在或不存在炎症激动剂的情况下，细胞因子/趋化因子的释放和白细胞的募集。2. 随后，我们将使用活体显微镜研究白细胞对动脉分叉的滚动和粘附。首先，我们将比较健康动物的直动脉区域和血管分叉，随后我们将研究ApoE/LDL受体双敲除小鼠（ApoE-/LDLR-）斑块上游和下游区域白细胞募集的区域差异。3. 斑块形成和不稳定的机制与局部血流模式和血管几何形状有关，将在大量的晚期人类颈动脉病变和事故受害者的动脉粥样硬化前颈动脉标本的纵向切片上进行研究。此外，在一项正在进行的关于代谢和结构斑块特征的PET/CT研究中，将分析斑块上游和下游区域炎症过程的强度。我们相信，计划中的研究结果将提高对动脉粥样硬化病理生理中血流介导过程的理解，并将有助于更精确地靶向动脉粥样硬化相关的内皮功能障碍和斑块不稳定。

Atherosclerotic plaque formation results from a combination of local blood flow patterns and inflammatory processes. This project focuses on the impact of hemodynamic forces in combination with inflammatory agonists on the development, progression, and destabilization of atherosclerotic lesions, and on the therapeutical possibilities of pharmacological modulation of these processes. 1. Using bifurcating flow-through cell culture slides we will expose endothelial cells to laminar or non-uniform shear stress at arterial level, in order to analyze important endothelial functions, such as release of cytokines/chemokines and recruitment of leukocytes under specific flow conditions, in the presence or absence of inflammatory agonists. 2. We will subsequently investigate the rolling and adhesion of leukocytes to arterial bifurcations in vivo using intravital microscopy. First, we will compare straight artery regions to vessel bifurcations in healthy animals, and subsequently we will investigate the regional differences in leukocyte recruitment between upstream and downstream regions of the plaques in ApoE/LDL receptor double-knockout mice (ApoE-/LDLR-). 3. The mechanisms of plaque formation and destabilization in relation to local flow patterns and vessel geometry will be investigated on a large number of longitudinal sections of advanced human carotid lesions and of pre-atheroma carotid specimens from victims of accidents. Moreover, the magnitude of inflammatory processes in upstream versus downstream regions of the plaques will be analyzed within an ongoing study regarding metabolic and structural plaque characterization by PET/CT. We believe that the results of the planned study will improve the understanding of flow-mediated processes in pathophysiology of atherosclerosis and will contribute to more precise pharmacological targeting of atherogenesis-related endothelial dysfunction and plaque destabilization.