Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells
Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells
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DOI：
10.2353/ajpath.2007.060693
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发表时间：
2007-04-01
影响因子：
6
通讯作者：
Ikeda, Eiji
中科院分区：
文献类型：
--
作者：
Koto, Takashi;Takubo, Keiyo;Ikeda, Eiji
缺氧诱导的神经血管屏障功能的破坏的机制进行了分析与参考的表达claudin-5，神经内皮细胞之间的紧密连接的一个组成部分。claudin-5从培养的融合脑源性内皮细胞（bEND.3）的细胞质到质膜的运动与跨内皮电阻的增加密切相关。通过RNAi抑制claudin-5的表达导致跨内皮电阻的降低，表明claudin-5在屏障性质中的关键作用。缺氧（1%O-2）改变了claudin-5在质膜中的位置和claudin-5蛋白在bEND.3细胞中的水平，并且这些变化伴随着跨内皮电阻的降低。在体内，紧密连接蛋白-5分子在常氧下在视网膜微血管内皮细胞的质膜中表达，但在缺氧条件下显著降低。示踪剂实验显示，具有抑制的claudin-5表达的缺氧视网膜血管系统的屏障功能针对小分子被选择性地破坏，这与claudin-5缺陷小鼠的表型非常相似。这些体外和体内数据表明，claudin-5是导致神经血管屏障功能破坏的缺氧的靶分子。
The mechanisms underlying the hypoxia-induced disruption of the barrier function of neural vasculature were analyzed with reference to the expression of claudin-5, a component of tight junctions between neural endothelial cells. The movement of claudin-5 from the cytoplasm to the plasma membrane of cultured confluent brain-derived endothelial (bEND.3) cells was closely correlated with the increase in the transendothelial electrical resistance. Inhibition of the expression of claudin-5 by RNAi resulted in a reduction of transendothelial electrical resistance, indicating a critical role of claudin-5 in the barrier property. Hypoxia (1% O-2) altered the location of claudin-5 in the plasma membrane and the level of claudin-5 protein in bEND.3 cells, and these changes were accompanied by a decrease in the transendothelial electrical resistance. In vivo the claudin-5 molecules were expressed under normoxia in the plasma membrane of retinal microvascular endothelial cells but were significantly reduced under hypoxic conditions. Tracer experiments revealed that the barrier function of hypoxic retinal vasculature with depressed claudin-5 expression was selectively disrupted against small molecules, which is very similar to the phenotype of claudin-5-deficient mice. These in vitro and in vivo data indicate that claudin-5 is a target molecule of hypoxia leading to the disruption of the barrier function of neural vasculature.