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（angiotensin Ⅱ，Ang Ⅱ）1型受体（AT_1）和2型受体（AT_2）在动脉粥样硬化形成中起重要作用，但骨髓AT_1和AT_2受体介导的作用尚不清楚。方法和结果：（1）动脉粥样硬化模型：ApoE-KO小鼠（apoE-KO/BM-Ag +^<-/+>）与apoE-KO/BM-Ag +^<+/+>小鼠相比，动脉粥样硬化病变明显减轻。单核细胞/巨噬细胞的积累在apoE-KO/BM-Agglutamine ^&lt;-/-&gt;小鼠中减弱，伴随着循环Ly-6C^单核细胞数量的减少<hi>。骨髓细胞的流式细胞术分析显示，apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的粒/巨噬细胞祖细胞数量明显减少，而造血干细胞（HSC）数量在两组之间没有差异，这表明BM-AT_1促进了apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的造血干细胞（HSC）数量的增加，而apoE-KO/BM-AgglutinA ^&lt;-/-&gt;小鼠的造血干细胞（HSC）数量的增加。 关于我们 从HSC向巨噬细胞祖细胞的转变。(2)血管修复模型;将来自Agtr 1 ^&lt;-/-&gt;、Agtr 2 ^&lt;-/-&gt;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-Agtr 2 &lt;-/-&gt;小鼠中的新生内膜形成显著增加，而BM-Agtr 2 &lt;-/-&gt;小鼠中的新生内膜形成低得多。在BM-Agtr 2 ^&lt;-/-&gt;小鼠中，由c-kit-/lin-/Sca-1^+标记物定义的循环潜在血管祖细胞显著减少，而CXR 4 ^+血管祖细胞显著增加。BM-AT_1与HSC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，导致从骨髓的动员增加和在血管修复部位的积聚。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一个有希望的治疗靶点。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