GTPCH/BH4通路在切应力调控内皮祖细胞修复高血压血管损伤中的作用与机制

The decreased endogenous endothelial repair capacity resulting from dysfunctioned circulating endothelial progenitor cells (EPCs) is the important mechanism underlying hypertension-related vascular injury. GTPCH/BH4 pathway plays an important role in modulating the adherion, migration and proliferation of EPCs. Our previous study indicates that shear stress can regulate the function of EPCs and subsequetly enhance the endogenous endotheial repair capacity. However, whether shear stress can modulate GTPCH/BH4 pathway of EPCs for repairing hypertension-related vascular injury 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 GTPCH/BH4 pathway and repair capacity of EPCs for hypertension-related vascular injury and its mechanism, studys the modulation of in vitro shear stress on GTPCH/BH4 pathway of EPCs and its association with EPC adherion, migration and proliferation, and investigates the the role of GTPCH/BH4 pathway in modulation of shear stress on the capacity of EPCs for repairing hypertension-related vascular injury and its mechanism. Therefore, this study for the first time put forwards that GTPCH/BH4 pathway is an important target of shear stress-mediated regulation of EPC function and subsequently accelerated repair capacity for hypertension-related vascular injury, providing the scientific evidence for shear stress-mediated cell therapy in the prevention and treatment of hypertension-related vascular diseases.

循环内皮祖细胞功能受损导致的内源性血管修复能力下降是高血压血管内皮损伤的重要机制，GTPCH/BH4通路是介导内皮祖细胞黏附、迁移和增殖功能的重要途径。我们的前期研究表明，切应力是调控内皮祖细胞功能及提升内源性抗血管损伤能力的重要手段，但切应力能否通过调控内皮祖细胞GTPCH/BH4通路修复高血压血管损伤尚不明了。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GTPCH/BH4通路与高血压内皮祖细胞促血管修复能力下降的关系及机制；研究体外切应力对内皮祖细胞GTPCH/BH4通路的调控机制及其与黏附、迁移和增殖功能的关系；探讨GTPCH/BH4通路在切应力调控内皮祖细胞修复高血压血管损伤中的作用及机制。本研究首次提出GTPCH/BH4通路是切应力调控内皮祖细胞功能并加快高血压血管损伤修复新的重要靶点，为切应力介导的细胞疗法防治高血压血管病变提供科学依据。

循环内皮祖细胞功能受损导致的内源性血管修复能力下降是高血压血管内皮损伤的重要机制，GTPCH/BH4通路是介导内皮祖细胞黏附、迁移和增殖功能的重要途径。在前期工作基础上，本课题采用生物力学、细胞生物学和分子生物学等多学科交叉方法，探讨GTPCH/BH4通路与高血压内皮祖细胞促血管修复能力下降的关系及机制；研究体外切应力对内皮祖细胞GTPCH/BH4通路的调控机制及其与黏附、迁移和增殖功能的关系；探讨GTPCH/BH4通路在切应力调控内皮祖细胞修复高血压血管损伤中的作用及机制。结果发现GTPCH/BH4通路是切应力调控高血压内皮祖细胞修复血管损伤的重要靶点，通过上调GTPCH/BH4通路能增加高血压内皮祖细胞功能，加快高血压血管内皮损伤修复。本项目还探讨了高血压前期、冠心病和糖尿病对内皮祖细胞功能的影响及其分子机制。发现合并糖尿病使绝经前高血压前期女性的循环内皮祖细胞数量和功能明显减低，引起血管内皮功能受损，其机制可能与Tie2/PI3K/Akt/eNOS通路异常磷酸化和GTPCH/BH4通路下调有关；发现与高血压前期男性相比，绝经前高血压前期女性循环内皮祖细胞数量和功能保持较高水平，表明维持较强的内源性血管损伤修复能力是绝经前高血压前期女性的血管保护机制之一；发现上调CXCR7基因能增加冠心病患者晚期内皮祖细胞的血管新生能力，提示CXCR7/p-ERK信号通路是调控冠心病内皮祖细胞促血管新生的重要靶点。发现Best-3对内皮细胞炎症的影响是内皮细胞NF-kB信号通路的内源性抑制剂，提示上调Best-3表达可能是抑制血管炎症反应和修复血管内皮损伤新的重要途径。发现ω-3多不饱和脂肪酸能抑制脑细胞ROS表达和减轻细胞死亡，从而保护脑损伤，是一种有效的神经保护的药物干预方法。因此，本研究表明切应力是介导内皮祖细胞修复高血压血管内皮损伤的重要策略，GTPCH/BH4通路是切应力调控内皮祖细胞功能并加快高血压血管损伤修复新的重要靶点，从而为切应力介导细胞修复高血压血管损伤提供了理论依据。