Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, University of California, Irvine, Orange, CA 92868, USA.
Neuron. 2014 May 7;82(3):603-17. doi: 10.1016/j.neuron.2014.03.003. Epub 2014 Apr 17.
Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.
脑内皮细胞通过紧密连接 (TJ) 和稀少的内吞小泡形成了对许多血源溶质的细胞旁和细胞内屏障。血脑屏障 (BBB) 在中枢神经系统的健康和疾病中起着关键作用。缺血性中风后的 BBB 损伤导致死亡率增加，但在体内，这种过程中细胞旁和细胞内机制的贡献尚不清楚。我们创建了一种转基因小鼠品系，其内皮 TJ 用 eGFP 标记，并使用双光子显微镜在 t-MCAO 中风模型中对活体 TJ 变化和荧光示踪剂渗漏进行了成像。尽管在中风后 6 小时内就已经出现了屏障功能受损，但 TJ 仅在 2 天后才显示出明显的结构缺陷。相反，内皮小窝的数量和转胞吞作用率在中风后 6 小时就开始增加。因此，细胞内屏障机制的逐步损伤随后是细胞旁屏障机制，导致中风时 BBB 缺陷。
