基于生物力学调控晚期内皮祖细胞STIM1通路改善糖尿病血管新生障碍的机制研究

The impaired angiogenesis cpacity resulting from attenuated activity of late endothelial progenitor cells (EPCs) is an important mechanism underlying diabetes mellitus-related ischemic vascular diseases. STIM1 pathway plays an significant role in modulating the function of migration, proliferation and tube formation of late EPCs. Our previous study indicates that shear stress can regulate the function of early EPCs and enhance the endogenous vascular endothelial repair capacity. However, whether shear stress can modulate STIM1 pathway of late EPCs to imporve impaired angiogenesis capacity in diabetes mellitus is still unkown. Based on our previous investigations, the study applys the interdisciplinarity method including biomechanics, cell biology and molecular biology, investigates the relationship between STIM1 pathway of late EPCs and impaired angiogenesis capacity in diabetes mellitus, studys the modulation of shear stress on STIM1 pathway of late EPCs in diabetes mellitus and its association with EPC migration, proliferation and tube formation function, and investigates the the role of STIM1 pathway in the regulation of shear stress on late EPCs for accelarated angiogenesis. Therefore, this study for the first time puts forwards that STIM1 pathway is an important target of shear stress-mediated regulation on the function of late EPCs and subsequently improvement in impaired angiogenesis capacity in diabetes mellitus, providing the novel strategy and idea of cell therapy in the prevention and treatment of diabetes mellitus-related ischemic vascular diseases.

晚期内皮祖细胞功能受损导致的血管新生障碍是糖尿病缺血性血管病变发生的重要机制，STIM1通路是介导晚期内皮祖细胞迁移、增殖和管型形成功能的重要途径。我们的前期研究表明，切应力是调控早期内皮祖细胞功能活性和增加内源性抗血管内皮损伤能力的重要手段，但切应力能否通过调控晚期内皮祖细胞STIM1通路改善糖尿病血管新生障碍尚不清楚。在前期工作基础上，本课题拟采用生物力学、细胞生物学和分子生物学等多学科交叉方法，探讨晚期内皮祖细胞STIM1通路与糖尿病血管新生障碍的关系，研究切应力对糖尿病晚期内皮祖细胞STIM1通路的调控机制及其与迁移、增殖和管型形成功能的关系，探讨STIM1通路在切应力调控糖尿病晚期内皮祖细胞促血管新生中的作用。本研究首次提出STIM1通路是切应力调控晚期内皮祖细胞功能并改善糖尿病血管新生障碍的重要靶点，从而为细胞疗法防治糖尿病缺血性血管疾病提供新的策略和思路。

晚期内皮祖细胞功能受损导致的血管新生障碍是糖尿病缺血性血管病变发生的重要机制，STIM1通路是介导晚期内皮祖细胞迁移、增殖和管型形成功能的重要途径。本课题探讨了STIM1通路在切应力调控糖尿病晚期内皮祖细胞促血管新生中的作用，发现STIM1通路是切应力调控糖尿病晚期内皮祖细胞体外功能及血管生成能力的重要靶点，通过上调STIM1通路能增加糖尿病晚期内皮祖细胞功能，改善糖尿病血管新生障碍。本项目还发现切应力通过调控PTEN/Akt/GTPCH/BH4通路上调晚期内皮祖细胞的血管生成能力，为糖尿病缺血性血管病变提供了新的潜在治疗靶点。同时，本项目发现支气管扩张患者存在循环内皮祖细胞数量和功能的缺陷，且和疾病的严重程度相关，揭示了支气管扩张患者高心血管事件发生风险的潜在机制。本项目还发现13-甲基小檗碱可以改善内皮损伤，可能与自噬抑制了NLRP3炎症小体的激活有关，为糖尿病血管内皮损伤防治提供新的药物干预策略。另外，本项目阐明了抑制HIF-1α/miR-674-5p/XBP-1信号通路可以减轻内毒素血症引起的肠道损伤。构建了脓毒症小鼠模型多器官的miRNA-mRNA调控网络，并预测了脓毒症多器官损伤的关键基因，为脓毒症多器官损伤提供新的干预靶点。因此，本研究表明切应力是介导晚期内皮祖细胞改善糖尿病血管新生障碍的重要策略，STIM1和PTEN通路是切应力调控晚期内皮祖细胞功能并促血管新生的重要靶点，从而为切应力介导细胞治疗糖尿病缺血性血管病变提供新的理论依据。