血管内膜增生是冠脉介入治疗后血管再狭窄的关键机制。我们新近发现转录因子GATA6调节WISP2控制损伤后内膜增生的形成。血管高表达WISP2，平滑肌特异敲除WISP2小鼠股动脉损伤后内膜增生显著增加，本课题拟用平滑肌特异过表达小鼠确认WISP2对内膜增生作用。有报导WISP2结合整合素αvβ3激活Src/FAK通路调节平滑肌功能，我们发现抑制αvβ3逆转WISP2敲除增加的平滑肌增殖迁移，进一步实验研究WISP2不同结构域与αvβ3特异结合，通过蛋白交联结合质谱筛选新的WISP2结合蛋白，探索WISP2不同结构域多肽及其结合分子对平滑肌细胞功能的影响。WISP2作为细胞基质蛋白在移植物和组织间起桥梁作用，抑制平滑肌增殖且不影响内皮功能。将WISP2或有功能WISP2结构域多肽及其结合分子作为支架涂层，大动物实验模型中验证其生物兼容性和对支架内狭窄防治作用，为PCI术后并发症治疗提供新方法。

In-stent restenosis (ISR) has always been considered the “enemy” for the interventional cardiologists, thus many technical improvements in the last 20 years aimed at reducing its occurrence, however, it is still the major cause of mortality, which indicates an urgent need for study of the underlying mechanisms to provide innovative treatment strategies..WISP2 is a matricellular protein highly expressed in vascular smooth muscle cells (VSMCs) and endothelial cells and proliferating VSMCs has significantly reduced expression. Our previous study showed that WISP2 was downstream target of transcription factor GATA6 and elevated expression in VSMCs reversed the enhanced injury-induced neointimal hyperplasia due to loss of GATA6. Therefore, in this study we constructed WISP2 conditional loss-of-function and gain-of function mice and crossed with VSMC specific inducible SM-MHCCreERT2 line to generate VSMC specific Wisp2 loss-of-function and gain-of function mice for further investigation of its function and mechanisms in injury-induced neointimal formation. VSMC-WISP2 loss-of-function mice exhibited increased neointimal hyperplasia after wire injury of femoral artery. This study we will use VSMC-WISP2 gain-of function mice to further confirm the cell specific regulatory effects of WISP2 on neointimal formation..Recent studies reported that WISP2 bound directly to integrin αvβ3 and regulated smooth muscle function through Src/FAK pathway. Our study found that inhibition of αvβ3 reversed the WISP2-deletion mediated enhanced VSMC proliferation and migration, suggesting that VSMC-WISP2 might regulate neointimal hyperplasia through αvβ3/Src/FAK signaling pathway, while no significant effect of WISP2 on endothelial function was observed. .In order to determine the mechanisms of WISP2, we constructed full length Wisp2 and its function domain IGFBP, VWC and TSP1 and will observe the domain specific binding of αvβ3 for regulation of VSMC function. Moreover, we will use protein crosslink combination with Mass Spectrometry to screen new functional binding partners..WISP2, a matricellular protein bridging between transplant grafts and tissues, inhibits smooth muscle proliferation without influencing endothelial function. Therefore, it is of great significance to explore WISP2, the screened positive functional domain peptides and binding partners as stent coating for treatment of in-stent restenosis in large animal model. .This study will advance our understanding of mechanisms of WISP2 in injury induced neointimal formation, meanwhile also provide opportunities for WISP2 associated protein as a novel stent coating for future therapeutic intervention of in-stent restenosis.