血管支架植入后力学环境变化影响血管支架内再狭窄和晚期血栓形成的机制研究

Endovascular stent implantation is the most important and effective cardiovascular interventional treatment. But the mechanisms of stent restenosis, late thrombosis and the delay of re-endothelialization are still not clearly known. Nevertheless, it has been well recognized that the fundamental cause to these problems is the alteration in the host artery’s mechanical environment resulted from stent implantation. This proposed research project intends to develop an in vivo artery-stent interaction mechanical model in the purpose of exploring the regularity of the stent-induced alteration in local vascular mechanical environment (flow shear stress, the stress distribution in the blood vessel wall and the mechanical properties of the vessel wall, etc). Based on this, the effects of the altered local mechanical environment of the blood vessel on the biological behaviors of endothelial cells, smooth muscle cells, dendritic cells and fibroblasts etc, as well as on the regulation of the expressions of the related genes and proteins will be investigated in vivo. Then, the project will establish a three dimensional cell co-culture model to clarify the correlation between the biological behaviors of the cells and the mechanical stimulus due to stent implantation and to explore the molecular mechanism of arterial stent restenosis. By this way, we will try to establish a theoretic basis to promote re-endothelialization and inhibit restenosis after stent implantation. This study might not only provide new ideas to clarify the mechanism of the restenosis and late thrombosis, but also provide a theoretical basis for the design of new stents.

血管支架植入是心血管介入治疗最重要且有效的治疗手段。然而，支架内再狭窄的发生和晚期血栓形成及再内皮化延迟的机理至今不明。尽管如此,支架植入后宿主血管局部力学环境变化是导致这些问题的根本原因已是不争的事实。本课题拟通过构建在体血管-支架两者之间相互作用的力学模型，探讨支架植入后血管局部力学环境（流动剪切应力、血管壁内应力分布、血管力学性质等）的变化规律，进而研究支架植入后力学环境改变对在体环境中内皮细胞、平滑肌细胞、树突状细胞和成纤维细胞等的生物学行为以及对相关基因和蛋白质调控的影响；通过构建三维共培养的生物力学模型探索力学与血管生物学之间的关系及力学变化对血管再狭窄影响的分子机制，为寻求既能促进血管再内皮化又能抑制血管支架内再狭窄的方法提供理论基础。本研究不仅能为阐明血管再狭窄和晚期血栓形成机理提供新的研究思路，也能为新型血管支架的设计提供理论依据。

血管支架植入是心血管介入治疗最重要且有效的治疗手段。然而，支架内再狭窄的发生和 晚期血栓形成及再内皮化延迟的机理至今不明。尽管如此，支架植入后宿主血管局部力学环境变化是导致这些问题的根本原因已是不争的事实。本课题通过构建血管-支架两者之间相互作用的体外、体内及计算机数值仿真力学模型，探讨了支架植入后血管局部力学环境（流动剪切应力、血管壁内应力分布、血管力学性质等）的变化规律，进而研究了支架植入后力学环境改变对内皮细胞、平滑肌细胞、巨噬细胞、树突状细胞等的生物学行为以及对相关基因和蛋白质调控的影响；探索了力学环境变化对血管再狭窄影响的分子机制。研究表明，支架植入后，会大大改变血管壁内应力分布，使其极不均匀；血管壁内应力分布受动脉粥样硬化斑块成分影响，大脂质斑块可使血管壁内表面出现严重的应力集中，钙化斑块的影响与其位置相关，当钙化斑块位于血管狭窄且靠近血管内表面时，破裂的危险性高；支架植入会在植入区域产生扰流，影响一氧化氮（NO）的分泌与输运，导致支架植入的血管区域NO浓度下降；支架植入引起的力学环境改变可影响血管细胞的生物学行为；血管损伤产生的炎症应答主要由巨噬细胞引起、炎症小体NLRP3在支架植入血管修复中起重要作用。本研究具有重要的理论意义，部分研究成果正在进行产品转化。