Analysis of the mechanisms for antiatherogenic effect of bone marrow AT2 receptor by using gene-targeted mice

目的：血管紧张素II (Ang II) 1型（AT_1）和2型（AT_2）受体在动脉粥样硬化发生中起关键作用；然而，骨髓（BM） AT_1和at_2介导的作用仍不明确。本研究旨在探讨脑机蛋白- at_1和脑机蛋白- at_2在动脉粥样硬化发生和血管修复中的作用。方法与结果：(1)动脉粥样硬化模型；用Agtrl^<-/->骨髓重组的ApoE-KO小鼠（ApoE-KO /BM-Agtrl^<-/->）与ApoE-KO /BM-Agtrl^<+/+>小鼠相比，动脉粥样硬化病变明显减少。apoE-KO/BM-Agtrl^<-/->小鼠单核/巨噬细胞的积累减弱，同时循环中Ly-6C^< ->单核细胞数量减少。流式细胞术分析显示，apoE-KO/BM- agtrl ^<-/->小鼠BM细胞中粒细胞/巨噬细胞祖细胞数量明显减少，而两组造血干细胞（hsc）数量无显著差异，提示BM- at_1促进了造血干细胞向巨噬细胞祖细胞的转变。(2)血管修复模型；将Agtr1^<-/->、Agtr2^<-/->或WT小鼠的总BM细胞移植到BM消融的WT中，并进行股动脉损伤。与BM-WT小鼠相比，BM-Agtr2^<-/->小鼠的内膜形成明显增加，而BM-Agtrl^<-/->小鼠的内膜形成明显减少。循环电位血管祖细胞（由c-kit-/lin-/ ca-1^+标记定义）在BM-Agtrl^<-/->小鼠中明显减少，而在BM-Agtr2^<-/->小鼠中CXR4^+血管祖细胞明显增加。结论：BM-AT_1与造血干细胞向巨噬细胞祖细胞和血管祖细胞的发育密切相关，而BM-AT_2可能调节单核/巨噬细胞和血管祖细胞的性质，导致骨髓动员增强和血管修复部位的积累。我们的研究表明，BM-AT_1和BM-AT_2可能是预防心血管事件的有希望的治疗靶点。少

Objective : The angiotensin II (Ang II) type 1 (AT_1) and type 2 (AT_2) receptor play a key roles in atherogenesis ; however, bone marrow (BM) AT_1 and AT_2-mediated actions remain undefined. The purpose of this study was to elucidate the effect of BM-AT_1 and BM-AT_2 on the pathogenesis of atherosclerosis development and vascular repair.Methods and Results : (1) Atherosclerosis model ; ApoE-KO mice reconstituted with Agtrl^<-/->marrow (apoE-KO/BM-Agtrl^<-/->) showed a significant reduction in atherosclerotic lesions compared with apoE-KO/BM-Agtrl^<+/+> mice. The accumulation of monocytes/macrophages was attenuated in apoE-KO/BM-Agtrl^<-/->mice, concomitant with a decrease in the number of circulating Ly-6C^<hi> monocytes. Flow cytometric analysis of BM cells showed that the number of granulocyte/macrophage progenitors was much lower in apoE-KO/BM-Agtrl^<-/->mice, whereas the number of hematopoietic stem cells (HSCs) did not differ between the two groups, suggesting that BM-AT_1 promot … More es the transition from HSCs to macrophage progenitors. (2) Vascular repair model ; Total BM cells from Agtr1^<-/->, Agtr2^<-/->, or WT mice were transplanted into BM-ablated WT and femoral arterial injury was performed. Neointimal formation was markedly increased in BM-Agtr2^<-/->compared with BM-WT mice, whereas it was much lower in BM-Agtrl^<-/->mice. Circulating potential vascular progenitor cells, defined by c-kit-/lin-/Sca-1^+ markers, were markedly decreased in BM-Agtrl^<-/->mice, whereas CXR4^+ vascular progenitor cells markedly increased in BM-Agtr2^<-/->mice.Conclusions : BM-AT_1 is closely implicated in the development of HSCs into macrophage progenitors and vascular progenitors, whereas BM-AT_2 is likely to modulate the property of monocyte/macrophage and vascular progenitors leading to the augmented mobilization from the bone marrow and accumulation at the site of vascular repair. Our study indicates that BM-AT_1 and BM-AT_2 could be a promising therapeutic target for the prevention of cardiovascular events. Less