血管内皮细胞对冠脉药物洗脱支架载药涂层的分子应答机制研究

It is well established that drug-eluting stents (DES) can drastically decrease the occurance of restenosis. However, as DES supresses the hyperplasia of smooth muscle cells (SMC),it also supresses the proliferation of endothelial cells, which results in the delayed healing of endothelium and the occurance of stent thrombosis.It has commonly been conceived that anti-proliferation drugs inhibited the reendothlization, however recent study showed that drug coating material could also influence the proliferation of endothelial cells.There still exists a blank in the area of endothelial cells' molecular response to the coatings. Our earlier work showed that material with favorable biological compatibility, self-assembled lay by lay chitosan/haparin coating,could not only promote endothelium recovery,but also upregulate the proliferation and anti-thrombus related genes. By employing the invitro(cell-coating co-cultavation) and invivo (implantation of drug-coated stent)models, this research dynamically observes the corresponding changes of the expression of proliferation, adhesion, anti-thrombus, inflammatory related molecules to the chitosan/haparin coating as well as the other two coatings(polyvinylidene polymer and poly lactic acid). This study compares the different stent-related vascular remodeling and endothelial function induced by different molecular response and explores the VEGFR2-PI3K/AKT-eNOS signal pathway during this process. By discovering the endothelial cells' molecular reponse to the coating of stents,we can lay the foundation of designing a more "endothelially-friendly" DES.

冠脉药物洗脱支架使介入治疗再狭窄率下降，但其抑制平滑肌细胞增殖同时也抑制内皮细胞增殖，引起内皮愈合延迟，增加支架内血栓发生。传统观点认为抗增殖药物抑制了内皮修复，但最新研究表明:载药涂层材料同样影响内皮细胞增殖。当前载药涂层对内皮细胞作用的分子机制尚未见系统研究。我们前期工作发现：生物相容性良好的聚合物材料(逐层自组装壳聚糖/肝素涂层)具有促内皮修复功能，上调内皮细胞增殖及抗栓基因。本研究以此为线索，在体外（涂层细胞共培养）、体内（涂层支架植入）两种模型上，观察壳聚糖/肝素涂层与当前常用的两种载药涂层（偏氟乙烯共聚物和聚乳酸）在内皮细胞增殖、抗栓和炎症分子表达的差异，及对VEGFR2-PI3K/AKT-eNOS信号通路的影响，通过病理及影像学比较由于分子应答不同所致支架局部血管重构及内皮功能的差异，本项目拟阐明内皮细胞对支架涂层材料应答的分子机制，为设计"内皮友好型"药物支架提供理论基础。

冠脉药物洗脱支架使介入治疗再狭窄率下降，但其抑制平滑肌细胞增殖同时也抑制内皮细胞增殖，引起内皮愈合延迟，增加支架内血栓发生。传统观点认为抗增殖药物抑制了内皮修复，但最新研究表明:载药涂层材料同样影响内皮细胞增殖。当前载药涂层对内皮细胞作用的分子机制尚未见系统研究。.本项目围绕支架涂层及内皮修复展开，分析了内皮细胞对不同高聚物涂层的分子应答，研发了新型羟丁基壳聚糖-CD133抗体涂层及姜黄素纳米粒载药涂层等多种新型材料，这些涂层均在体外及动物实验中论证有效加快支架植入后内皮修复，动物实验提示可同时减少支架内膜增生。.在本项目开展过程中，冠脉介入支架领域研发重点已逐步聚焦于完全可降解支架，临床研究中亦提示可降解支架同样存在内皮修复延迟。故本项目在研究过程中亦着手于解决镁合金可降解支架生理条件下降解不稳定，炎症反应强，内皮修复不佳等问题，率先研发MgF2表面涂层、JDBM-2可降解合金等新型材料，有效提高了镁支架降解稳定性及内皮修复速度。.本研究重视临床基础有机结合，通过对支架植入患者长期随访血清相关因子的分析发现VEGF在晚期再狭窄患者中显著降低，并与再狭窄分型相关。而嗜酸性粒细胞阳离子蛋白在植入永久涂层支架患者中水平明显升高，提示了涂层诱导嗜酸性粒细胞激活是支架内再狭窄的潜在通路。另外，本研究亦资助多项临床转化医学研究，包括三氧化二砷药物洗脱支架，XINSORB可降解支架的探索性研究，在国内支架研发处于领先地位。.尽管研究方案较原设计存在一定调整，但本项目始终紧扣支架涂层及内皮修复的相互关系，在创新药物涂层、可降解支架及支架远期不良事件机制方面取得了一系列原创性成果，并发表10篇SCI论文，申报并获得专利1项。基本达成预期研究目标，并为继续设计和研发"内皮友好型"药物支架提供理论和实践基础。