NMII亚型调控内皮细胞粘附连接重塑影响血管生成机制研究

VE-cadherin（VE-cad）介导的粘附连接（AJs）重塑在血管生成中起关键作用。已知NMII调控VE-cad表达模式，但作用机制并不清楚。NMIIA（IIA）和NMIIB（IIB）是NMII重链的两个亚型。我们最近发现，在P6视网膜中IIA在血管生成前沿部位高表达而IIB主要在中央丛血管表达；敲低IIA和IIB影响了VE-cad表达模式和肌动球蛋白活性；敲低IIA促进而敲低IIB降低了细胞迁移。我们推测IIA和IIB通过差异性调控AJs动态学变化影响细胞迁移从而调控血管生成。本研究拟从细胞和分子生物学水平探讨IIA和IIB对AJs的调控作用和其机制，以及阐明调控IIA和IIB表达的分子机制，采用条件性基因敲除鼠揭示IIA/IIB-AJs信号轴在血管生成中的作用。本项目将从机械张力角度阐明调控AJs重塑的分子机制及血管生成机制，这将为血管生成相关疾病药物研发提供依据。

The remodeling of adherens junctions (AJs) mediated by VE-cadherin is essential for development of angiogenesis. It has been recently shown that NMII mediated mechanical stress regulates VE-cadherin expression pattern, but how NMII regulates AJs remains unknown. NMIIA (IIA）and NMIIB (IIB) are the two isoforms of NMII heavy chain. We recently showed that (1) IIA was enriched in angiogenic front ECs while IIB mainly expressed in center plexus ECs in P6 mice retina; (2) knock-down NMIIA or NMIIB impacted VE-cadherin expression pattern and actomyosin activity; (3) knock-down NMIIA augmented but down-regulation NMIIB decreased cell migration. Based on our findings, we speculated that IIA and IIB differentially regulates angiogenesis by distinctly modulating AJs dynamics. This present study aims to demonstrate the role and mechanism of IIA and IIB on AJs remodeling, clarify the molecular mechanisms controlling IIA and IIB expression, and uncover the impact of IIA/IIB-AJs axis on angiogenesis using IIA/IIB conditional knock-out mice. This project will reveal the molecular mechanism of AJs remodeling and angiogenesis from the perspective of mechanical stress, and eventually, provide a novel theoretical and experimental basis for the development of angiogenesis-related drugs.