GDF11通过动员及活化内皮祖细胞促进支架内皮化的实验研究

心血管支架置入后内皮化不全是术后再狭窄和血栓形成的主要原因。内皮祖细胞（EPCs）在支架内皮化中发挥着关键作用。但如何高效动员和活化EPCs并促进其富集在支架表面仍是目前的技术瓶颈。我们前期通过生物信息学分析发现生长分化因子11（GDF11）是影响EPCs生物学活性、促进支架内皮化的关键分子,并具有负调控ITGA4、激活Notch通路的作用。因此推测GDF11可能通过负调控ITGA4促进EPCs从骨髓动员至循环中，并通过激活Notch通路增强EPCs的生物学活性,GDF11可能分别从EPCs动员及活化这两个阶段参与支架内皮化的过程。本项目拟通过体内体外实验，并建立条件敲除及谱系示踪小鼠，在分子、细胞、动物多水平分析GDF11对EPCs促进支架内皮化中的作用和分子机制，为发现影响支架内皮化新的干预靶标提供理论依据。

Incomplete stent endothelialization after cardiovascular stent placement is the main cause of thrombosis and restenosis. Endothelial progenitor cells (EPCs) play a key role in repairing damaged blood vessels and accelerating endothelialization of the stent. But how to effectively mobilizes and activates EPCs as well as promotes the recruitment of EPCs onto stent remain to be elusive. We have previously found via bioinformatics that growth differentiation factor 11 (GDF11) is a key molecule affecting the biological activity of endothelial progenitor cells and the endothelialization of Nitinol stent, and GDF11 was found to be involved in negatively regulating the levels of ITGA4 as well as in the activation of Notch signal pathway.We speculate that GDF11 promotes the mobilization of EPCs from bone marrow into peripheral circulation through negatively regulating ITGA4. Moreover, GDF11 also promoted the activation of EPCs via Notch signaling pathway. Therefore, we propose that GDF11 may participate in the process of stent endothelialization via distinct two stages, namely mobilization and activation of EPCs. This study is designed to explore the functional role and molecular mechanism of GDF11 upon EPCs directed stent endothelialization via wide-range and multilevel stages including in vivo and in vitro approaches as well as establishing conditionally knockout and genetic lineage tracing mice. This study will provide a theoretical basis for discovering new intervention targets that affect stent endothelialization.