Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2
Collateral artery growth (arteriogenesis) after experimental arterial occlusion is impaired in mice lacking CC-chemokine receptor-2
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DOI：
10.1161/01.res.0000122041.73808.b5
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发表时间：
2004-03-19
影响因子：
20.1
通讯作者：
Schaper, W
中科院分区：
文献类型：
--
作者：
Heil, M;Ziegelhoeffer, T;Schaper, W
动脉形成与侧支血管壁中单核/巨噬细胞的存在有关。巨噬细胞在体内的迁移是由单核细胞趋化蛋白-1(MCP-1，新命名为CCL2)与巨噬细胞表面CCR2-趋化因子受体结合所驱动的。为了确定CCL2-CCR2信号通路是否参与了巨噬细胞在生长的侧支血管中的积累，我们使用了CCR2缺乏的小鼠作为实验性动脉闭塞和侧支血管生长的模型。在体外CCL2诱导的趋化实验中，从野生型BALB/c小鼠分离的单个核细胞表现出CCL2浓度依赖的迁移，而来自CCR2(-/-)小鼠的这种迁移在BALB/c遗传背景下被取消。在体内，通过激光多普勒(LDI)和核磁共振(MRI)测量的血流恢复在BALB/c或C57BL/6遗传背景的CCR2(-/-)小鼠中受到损害。股动脉结扎后3周，BALB/c野生型小鼠后肢远端LDI灌注率增加到0.45+/-0.06，CCR2(-/-)组仅增加到0.21+/-0.03(P<0.01)。在C57BL/6小鼠中，这一比例分别增加到0.96+/-0.09和0.85+/-0.08(P<；0.05)。3周时的MRI(0.76+/-0.06比0.62+/-0.01；P<；0.05)和血红蛋白血氧饱和度测量证实了这些发现。CCR2(-/-)小鼠主动足部运动评分明显降低，腓肠肌萎缩明显加重。形态计量学分析显示CCR2(-/-)小鼠侧支血管直径增加较少。重要的是，与野生型小鼠相比，CCR2(-/-)动物侧支动脉血管周围间隙中入侵的单核/巨噬细胞数量显著减少。综上所述，我们的结果表明CCR2信号通路对于有效的侧支动脉生长是必不可少的。
Arteriogenesis has been associated with the presence of monocytes/ macrophages within the collateral vessel wall. Induced macrophage migration in vivo is driven by the binding of monocyte chemoattractant protein- 1 ( MCP- 1, or CCL2 in the new nomenclature) to the CCR2- chemokine receptor on macrophages. To determine whether the CCL2- CCR2 signaling pathway is involved in the accumulation of macrophages in growing collateral vessels, we used mice that are deficient in CCR2 in a model of experimental arterial occlusion and collateral vessel growth. In an in vitro CCL2- driven chemotaxis assay, mononuclear cells isolated from wild- type BALB/ c mice exhibited CCL2 concentration - dependent migration, whereas this migration was abolished in cells from CCR2(-/-) mice on a BALB/ c genetic background. In vivo, blood flow recovery as measured by laser Doppler ( LDI) and MRI ( MRI) was impaired in CCR2(-/-) mice on either the BALB/ c or C57BL/ 6 genetic backgrounds. Three weeks after femoral artery ligation, LDI perfusion ratio of operated versus nonoperated distal hindlimb in BALB/ c wild- type mice increased to 0.45 +/- 0.06 and in CCR2(-/-) animals only to 0.21 +/- 0.03 ( P < 0.01). In C57BL/ 6 mice, ratio increased to 0.96 +/- 0.09 and 0.85 +/- 0.08 ( P < 0.05), respectively. MRI at 3 weeks ( 0.76 +/- 0.06 versus 0.62 +/- 0.01; P < 0.05) and hemoglobin oxygen saturation measurements confirmed these findings. Active foot movement score significantly decreased and gastrocnemius muscle atrophy was significantly greater in CCR2(-/-) mice. Morphometric analysis showed a lesser increase in collateral vessel diameters in CCR2(-/-) mice. Importantly, the number of invaded monocytes/ macrophages in the perivascular space of collateral arteries of CCR2(-/-) animals was dramatically reduced in comparison to wild- type mice. In conclusion, our results demonstrate that the CCR2 signaling pathway is essential for efficient collateral artery growth.