SFRP5对高血压相关性靶器官损害的影响及其作用机制研究

Arterial stiffness gradient and capillary rarefacton are two principal mechanism of the hypertensive target organ damage. We have proven in our previous study that SFRP5 was expressed differentially between the central and peripheral arteries, and could affect the migration and proliferation of the vascular smooth muscle cell (VSMC), as well as its low-degrade inflamation level, via the WNT/β-catenin pathway. On the other hand, current investigations indicated that, under metabolic dysturburse, SFRP5 could facilliate capillary angiogenesis in adipose tissue via the WNT5a-VEGF-A165b pathway. Moreover, our preliminary study also indicated that SFRP5 could significantly influence capillary angiogenesis in micro-circulation. According to these facts, we hypothesize that SFRP5 play an important role in the mechanism of hypertensive target organ damage, because it may influence the arterial stiffness gradient between the central and peripheral arteries through the discrepant experession in the perivascular adipose tissue, as well as facilliate capillary rarefaction through blocking the capillary angiogenesis in the micro-circulation. The present study is designed to investigate the role of SFRP5 in the arterial stiffness gradient and capillary rarefaction by using the SFRP5 knock-out and gene over-expression animal models, and also to study the effect of SFRP5 on the function of VSMC and vascular endothelial cell (VEC), and the related singal pathway.The present study would provide novel theoretical basis and therapeutic target to the development of the organ-protective antihypertensive therapy.

高血压相关靶器官损害的两大核心机制是中心及外周动脉硬化不同步和微循环毛细血管稀疏。我们的前期研究证实，新兴抗炎脂肪因子SFRP5在中心与外周动脉周围存在显著的表达差异，且SFRP5可通过WNT/β-catenin通路影响VSMC内的慢性炎症反应及其迁移和增殖。另一方面，新近研究显示SFRP5可通过WNT5a-VEGF-A165b促进脂肪组织内毛细血管新生。我们的预实验也证实，SFRP5显著影响微循环内的毛细血管新生。据此，我们推测：SFRP5是高血压相关靶器官损害的关键调节蛋白，它不仅可通过在动脉周围的表达差异影响中心与外周的动脉硬化进程，还可在微循环内促进毛细血管稀疏。本项目拟利用SFRP5敲除及基因过表达动物模型深入研究SFRP5与动脉硬化不同步及毛细血管稀疏的关系，并在细胞水平探讨SFRP5对VSMC和内皮细胞功能的影响及其作用通路，从而为靶器官损害的药物研发提供理论依据及治疗靶点。

高血压是最常见的慢性疾病之一，长期的高血压状态可进一步引起重要靶器官的损害，包括血管和心脏损伤。我们在前期研究中发现新型抗炎因子SFRP5可能通过WNT/β-catenin 通路及MAPK通路抑制主动脉平滑肌细胞的增殖和迁移功能，从而影响动脉硬化的进程。而且通过本课题研究证明SFRP5促进血管内皮细胞增殖、迁移和血管新生，从而在微循环障碍中起到作用。同时，老年人群血清SFRP5水平降低与动脉硬化风险的增加显著相关，提示SFRP5在血管损伤中的保护作用。除此之外，人群研究中发现SFRP5与心功能的显著相关性，并通过动物实验初步证实SFRP5对心脏功能的保护作用。根据研究结果，我们认为SFRP5可能是高血压相关靶器官损害中的关键调节蛋白，从而为靶器官损害的药物研发提供理论依据及治疗靶点。