切应力促高血压内皮祖细胞修复血管内皮损伤的作用与机制研究

Vascular endothelial injury is one of initiating factors in occurrence and development of hypertesion.To replace dysfunctional endothelium and to preserve the structurally and functionally intact endothelium is the key point in controlling hypertension. Impoving the function of endothelial progenitor cell（EPC）is considered as a significant strategy to accelerate the repairment of vascular injury. The study will apply the experimental model of cell culture in vitro,animal carotid artery injured model,shear stress model and clinical investigation via multidisciplinary techniques such as cytobiology molecular biology, histochemistry, pathology, RNA interference and so on, to explore the role of shear stress to promote hypertensive endothelial injury repair. Then,we study the effect of shear stress on the chemokine receptor 7/stromal cells derived factor-1（CXCR7/SDF-1）signal pathway in the homing of EPCs to the vascular inury sites and its relation to EPC-based reendothelialization.The study first put forward the novel target and underlying mechanism of shear stress-accelerated the repairment of vascular injury, and may provide a new theoretical basis and clinical practice potential of shear strss and exercise for the prevention and treatment of hypertensive vascular injury.

血管内皮损伤是高血压发生发展的始动因素之一，提高循环内皮祖细胞归巢能力并定植到损伤部位，从而加速损伤动脉再内皮化是修复高血压血管内皮损伤的重要方法。我们前期研究发现，切应力是调节细胞功能的重要手段，高血压患者内皮祖细胞功能损伤，但切应力对高血压内皮祖细胞修复内皮损伤能力的影响与相关分子机制有待进一步探讨。因此，本研究采用细胞生物学、分子生物学、免疫组织化学、血管病理学及siRNA 干扰等多学科交叉方法，从体外细胞模型、颈动脉拉脱动物模型、低切应力模型和临床试验四个方面，研究切应力促高血压内皮祖细胞修复血管内皮损伤的作用，探讨趋化因受体7（CXCR7）信号通路在切应力介导内皮祖细胞归巢的分子机制及其与修复血管内皮损伤的关系。本课题首次开展切应力调控CXCR7保护血管内皮新的作用靶点和机制研究，为切应力和运动调控内皮祖细胞防治高血压血管内皮损伤提供实验依据和应用基础。

以内皮祖细胞为基础的干细胞疗法是修复血管内皮损伤的重要方法，切应力是提高内皮祖细胞功能加快血管损伤修复的重要手段，但分子生物学机制尚不明了。本课题采用 Flow Chamber 切应力装置和腺病毒基因转染等分子生物学技术，建立体外细胞培养模型、血管损伤修复模型、切应力模型和RIPC模型，研究CXCR7/p38MAPK/Cleaved Caspase3信号通路在介导高血压内皮祖细胞归巢至局部血管损伤中的作用和分子机制；探讨钙拮抗剂和切应力调控内皮祖细胞、内皮细胞CXCR7信号传导通路对其增殖、迁移、粘附和再内皮化功能的影响。本研究首次提出CXCR7/p38MAPK/Cleaved Caspase3信号通路是钙拮抗剂和切应力调控内皮祖细胞增殖、迁移、粘附、凋亡从而加快损伤血管修复的重要靶点，为切应力介导细胞疗法防治血管疾病提供新的分子生物学理论依据。