Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke.
Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke.
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DOI：
10.1083/jcb.201212032
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发表时间：
2013-07-22
期刊：
影响因子：
--
通讯作者：
Strickland S
中科院分区：
文献类型：
--
作者：
Chen ZL;Yao Y;Norris EH;Kruyer A;Jno-Charles O;Akhmerov A;Strickland S
星形细胞层粘连蛋白的消融破坏了血管平滑肌细胞和星形胶质细胞之间的相互作用，下调了收缩蛋白的表达，削弱了脑深部区域的血管完整性，导致出血。星形胶质细胞表达层粘连蛋白，并在其末端组装基底膜，包裹着脑血管系统。星形细胞层粘连蛋白在脑血管完整性中的作用尚不清楚。我们发现，通过组织特异性CRE介导的重组来消融星形细胞层粘连蛋白，破坏了成年小鼠的终足骨髓间质，并导致脑深部出血，类似于人类高血压出血。星形细胞层粘连蛋白的缺乏导致血管平滑肌细胞(VSMCs)功能受损，星形胶质细胞与小动脉中的VSMCs联系更紧密，并与出血的血管相关，表现为VSMC碎裂和血管壁解体。成年小鼠纹状体星形细胞层粘连蛋白的急性破坏也损害了VSMC的功能，表明层粘连蛋白是维持VSMC所必需的。在体外，星形胶质细胞和星形胶质细胞层粘连蛋白均促进脑VSMC分化。这些结果表明，星形胶质细胞调节VSMCs和脑深部小血管的血管完整性。因此，星形胶质细胞可能是出血性卒中预防和治疗的一个可能靶点。
Ablation of astrocytic laminin disrupted the interaction between vascular smooth muscle cells and astrocytes, down-regulated contractile protein expression, and weakened vascular integrity in deep brain regions, leading to hemorrhage. Astrocytes express laminin and assemble basement membranes (BMs) at their endfeet, which ensheath the cerebrovasculature. The function of astrocytic laminin in cerebrovascular integrity is unknown. We show that ablation of astrocytic laminin by tissue-specific Cre-mediated recombination disrupted endfeet BMs and led to hemorrhage in deep brain regions of adult mice, resembling human hypertensive hemorrhage. The lack of astrocytic laminin led to impaired function of vascular smooth muscle cells (VSMCs), where astrocytes have a closer association with VSMCs in small arterioles, and was associated with hemorrhagic vessels, which exhibited VSMC fragmentation and vascular wall disassembly. Acute disruption of astrocytic laminin in the striatum of adult mice also impaired VSMC function, indicating that laminin is necessary for VSMC maintenance. In vitro, both astrocytes and astrocytic laminin promoted brain VSMC differentiation. These results show that astrocytes regulate VSMCs and vascular integrity in small vessels of deep brain regions. Therefore, astrocytes may be a possible target for hemorrhagic stroke prevention and therapy.
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