Sema4D/PlexinB1通过调控周细胞PDGF-Shh信号促进脑梗死后新生血管稳定和管壁肌化

脑梗死后新生血管稳定、成熟对患者长期预后至关重要。我们发现：大鼠脑梗死区域自发性新生血管无法形成成熟管腔，提供有效血流灌注，与Sema4D/Plexin-B1和 PDGF-Shh信号调控周细胞活动密切相关。本项目拟在In vivo 和 In vitro 情况下，采用基因敲除小鼠、磁共振灌注显像、荧光示踪等多种试验方法，探讨脑梗死后Sema4D/Plexin-B1和 PDGF-Shh信号动态变化规律，确定其与周细胞迁移、贴附和转化的调控关系，讨论脑梗死后，缺血缺氧诱导神经元高表达Sema4D调控PDGF激活周细胞Shh-Ang-1/Tie-2信号途径诱导周细胞贴壁、稳定新生管腔；激活Shh-Gli1-α-SMA信号途径促进周细胞转化、管壁肌化，加强血管收缩功能的具体分子机制。探讨以Sema4D为治疗靶点，诱导脑梗死后新生血管成熟和管壁肌化，最终重建血运、改善预后，为脑梗死治疗提供新线索。

The stability and maturity of vascular structures following angiogenesis after cerebral infarction is very important for the long-term prognosis. We found that effective blood perfusion resulting from spontaneous angiogenesis maturation, which may be closely related with the dysfunction of pericytes regulated by Sema4D/Plexin-B1 and PDGF-Shh signal transduction. This project aims to explore the dynamic change in Sema4D/Plexin-B1 and PDGF - Shh signals and mechanism of migration, adhesion and transformation of pericytes controlled by Sema4D/Plexin-B1 and PDGF - Shh, using knockout mice, MR perfusion weighted imaging, fluorescence tracerand so on , both In vivo and In vitro conditions. We also detected that, during ischemic insults, neurons could highly express Sema4D, which induced pericytes attached to the tube to form a stable new lumen by PDGF-Shh-Ang-1/Tie-2, as well as promoted pericytes transformation and strengthened vascular contraction by PDGF-Shh-Gli-1/α-SMA. Our study is to explore Sema4D as a potential therapeutic target to induce angiogenesis forming mature vascular and provide effective blood perfusion after stroke.