髓系AT1受体调控巨噬细胞功能极性及其在盐敏感性高血压血管损伤中的作用和机制研究

研究表明激活免疫细胞(如单核巨噬细胞）可促进高血压和血管损伤，但相关机制目前还不清楚。我们前期结果提示刺激髓系细胞AT1R可通过HIF1a通路激活巨噬细胞，在盐敏感性高血压大鼠AT1R阻断剂抑制巨噬细胞激活并减少其在血管壁浸润，改善血管内皮依赖性舒张功能。据此，我们提出假设：AT1R通过HIF1a/TLR4/NFkB信号通路调控巨噬细胞功能极性，在盐敏感性高血压上调髓系AT1R引起单核巨噬细胞激活以及在血管组织中浸润释放炎性因子, 并促进高血压和血管舒张功能障碍。本项目拟阐明: a)AT1R调控巨噬细胞功能极性的分子细胞机制；b)在盐敏感性高血压引起单核巨噬细胞激活及血管组织浸润的机制；c)髓系细胞AT1R在盐诱导的血压升高及血管内皮功能障碍中的作用。本项目将从新的角度揭示单核巨噬细胞激活的新途径以及免疫细胞引起高血压和血管损伤的发病新机制，并有可能为高血压的免疫抑制疗法提供新的分子靶点。

It has been shown that activated immune cells (e.g. monocyte/macrophages) may promote hypertension and its associated vascular injury, however underlying the mechanisms are not defined. Our preliminary results suggest that stimulation of myeloid angiotensin type 1 receptor (AT1R) can activate macrophage through hypoxia inducible factor 1, AT1R blockers inhibited macrophage activation and infiltration in the vascular wall, improved endothelial function in salt-sensitive hypertensive rat. Accordingly, we hypothesize that AT1R controls macrophage polarization throguh HIF1a/TLR4/NFkB pathway, and in salt-sensitive hypertension upregulation of myeloid AT1R induce monocyte/macrophage activation, infiltration and release of inflammatory cytokines in the vascular walls, leading to acceleration of hypertension and vascular dysfunction. The project will clarify: a) the cellular and molecular mechnisms of myeloid AT1R in control of macrophage polarization; b) the mechanisms of monocyte/macrophage activation, infiltration into vascular wall in salt-induced hypertension; c) the role of myeloid AT1R in salt-induced elevation of blood pressure and endothelial dysfunction. The proposed studies may reveal a new signaling pathway leading to macrophage activation and insight into new mechanisms of immune cells-induce hypertension and vascular injury. The results from the proposed studies may discover a new molecular target for immunosuppressive therapy of hypertension.