Critical roles of macrophages in the formation of intracranial aneurysm.
Critical roles of macrophages in the formation of intracranial aneurysm.
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DOI：
10.1161/strokeaha.110.590976
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发表时间：
2011-01
期刊：
影响因子：
8.3
通讯作者：
Hashimoto T
中科院分区：
文献类型：
--
作者：
Kanematsu Y;Kanematsu M;Kurihara C;Tada Y;Tsou TL;van Rooijen N;Lawton MT;Young WL;Liang EI;Nuki Y;Hashimoto T
血流动力学应激和炎症引起的血管重构异常被认为是颅内动脉瘤病理生理的关键过程。大量的研究表明，炎症细胞，特别是巨噬细胞浸润到人颅内动脉瘤壁上。利用小鼠颅内动脉瘤模型，我们测试了巨噬细胞是否在颅内动脉瘤的形成中起关键作用。将弹性蛋白酶单次注入脑脊液和血管紧张素- ii诱导的高血压相结合，在成年雄性小鼠中诱导颅内动脉瘤。三周后评估动脉瘤形成情况。利用氯膦酸脂质体诱导巨噬细胞耗竭来评估巨噬细胞的作用。此外，在缺乏单核细胞趋化蛋白-1 （MCP-1, CCL2）的小鼠和缺乏基质金属蛋白酶-12 （MMP-12，巨噬细胞弹性酶）的小鼠中，评估动脉瘤的发生率。该模型颅内动脉瘤可见白细胞浸润至瘤壁，白细胞以巨噬细胞为主。巨噬细胞缺失小鼠动脉瘤发生率明显低于对照组（1/10 vs. 6/10; P < 0.05）。同样，与野生型小鼠相比，缺乏MCP-1小鼠的动脉瘤发生率降低（2/10比14/20，P < 0.05）。在缺乏MMP-12的小鼠和野生型小鼠之间，动脉瘤的发生率没有差异。这些数据提示巨噬细胞和适当的巨噬细胞功能在该模型颅内动脉瘤形成中的关键作用。
Abnormal vascular remodeling triggered by hemodynamic stresses and inflammation is believed to be a key process in the pathophysiology of intracranial aneurysms. Numerous studies have shown infiltration of inflammatory cells, especially macrophages, into intracranial aneurysmal walls in humans. Using a mouse model of intracranial aneurysms, we tested whether macrophages play critical roles in the formation of intracranial aneurysms. Intracranial aneurysms were induced in adult male mice using a combination of a single injection of elastase into the cerebrospinal fluid and angiotensin-II-induced hypertension. Aneurysm formation was assessed three weeks later. Roles of macrophages were assessed utilizing clodronate liposome-induced macrophage depletion. In addition, the incidence of aneurysms was assessed in mice lacking monocyte chemotactic protein-1 (MCP-1, CCL2), and mice lacking matrix metalloproteinase-12 (MMP-12, macrophage elastase). Intracranial aneurysms in this model showed leukocyte infiltration into the aneurysmal wall, the majority of leukocytes being macrophages. Mice with macrophage depletion had a significantly reduced incidence of aneurysms compared to control mice (1/10 vs. 6/10; P < 0.05). Similarly, there was a reduced incidence of aneurysms in mice lacking MCP-1, compared to incidence of aneurysms in wild-type mice (2/10 vs. 14/20, P < 0.05). There was no difference in the incidence of aneurysms between mice lacking MMP-12 and wild-type mice. These data suggest critical roles of macrophages and proper macrophage functions in the formation of intracranial aneurysms in this model.