Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 240 W Green Street, Athens, GA, 30602, USA.
Emergency Department, West China Hospital, 37 Guoxue Road, Chengdu, 610041, China.
Transl Stroke Res. 2020 Apr;11(2):228-242. doi: 10.1007/s12975-019-00709-8. Epub 2019 Jun 18.
Brain pericytes synthesize and deposit laminin at the blood-brain barrier (BBB). The function of pericyte-derived laminin in BBB maintenance remains largely unknown. In a previous study, we generated pericytic laminin conditional knockout (PKO) mice, which developed BBB breakdown and hydrocephalus in a mixed genetic background. However, since hydrocephalus itself can compromise BBB integrity, it remains unclear whether BBB disruption in these mutants is due to loss of pericytic laminin or secondary to hydrocephalus. Here, we report that, in C57Bl6 dominant background, the PKO mice fail to show hydrocephalus, have a normal lifespan, and develop BBB breakdown in an age-dependent manner. Further mechanistic studies demonstrate that abnormal paracellular transport, enhanced transcytosis, decreased pericyte coverage, and diminished AQP4 level are responsible for BBB disruption in PKO mice. These results suggest that pericyte-derived laminin plays an indispensable and age-dependent role in the maintenance of BBB integrity under homeostatic conditions.
脑周细胞在血脑屏障 (BBB) 处合成并沉积层粘连蛋白。周细胞衍生的层粘连蛋白在 BBB 维持中的功能在很大程度上尚不清楚。在之前的一项研究中，我们生成了周细胞层粘连蛋白条件性敲除 (PKO) 小鼠，这些小鼠在混合遗传背景下出现 BBB 破裂和脑积水。然而，由于脑积水本身可能会损害 BBB 的完整性，因此尚不清楚这些突变体中的 BBB 破坏是否是由于周细胞层粘连蛋白的缺失，还是继发于脑积水。在这里，我们报告说，在 C57Bl6 显性背景下，PKO 小鼠不会出现脑积水，具有正常的寿命，并以年龄依赖的方式出现 BBB 破裂。进一步的机制研究表明，异常的细胞旁转运、增强的转胞吞作用、周细胞覆盖减少和 AQP4 水平降低是 PKO 小鼠 BBB 破坏的原因。这些结果表明，在稳态条件下，周细胞衍生的层粘连蛋白在维持 BBB 完整性方面发挥不可或缺且年龄依赖性的作用。
