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

动脉粥样硬化斑块形成和不稳定过程中血流动力学与炎症过程之间的相互作用

• 批准号: 61703388
• 负责人: Professorin Dr. Iwona Cicha, Ph.D.
• 金额: --
• 依托单位: Sektion für Experimentelle Onkologie und Nanomedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/61703388?language=en
• 关键词: interplay; between; hemodynamic; forces; inflammatory

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.

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。该项目的重点是血流动力学的影响，结合炎症激动剂的发展，进展和动脉粥样硬化病变的不稳定，以及对这些过程的药理学调制的治疗可能性。1.使用分叉流通细胞培养载玻片，我们将内皮细胞暴露于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，例如在存在或不存在炎性激动剂的情况下，在特定流动条件下细胞因子/趋化因子的释放和白细胞的募集。2.随后，我们将研究滚动和粘附的白细胞在体内动脉分叉使用活体显微镜。首先，我们将比较健康动物的直动脉区域与血管分叉，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之间白细胞募集的区域差异。3.斑块的形成和不稳定的机制与局部流动模式和血管几何形状将研究大量的纵向部分先进的人类颈动脉病变和动脉粥样硬化前颈动脉标本的受害者的事故。此外，将在正在进行的关于PET/CT代谢和结构斑块表征的研究中分析斑块上游与下游区域的炎症过程的程度。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学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的药理学。