Tyrosine phosphatase inhibition induces loss of blood-brain barrier integrity by matrix metalloproteinase-dependent and -independent pathways
Tyrosine phosphatase inhibition induces loss of blood-brain barrier integrity by matrix metalloproteinase-dependent and -independent pathways
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DOI：
10.1016/j.brainres.2003.10.002
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发表时间：
2004-01-09
期刊：
影响因子：
2.9
通讯作者：
Galla, HJ
中科院分区：
文献类型：
--
作者：
Lohmann, C;Krischke, M;Galla, HJ
脑毛细血管内皮细胞之间的紧密连接形成了血脑屏障（BBB）的结构基础，血脑屏障控制着血液和CNS之间的分子交换。细胞屏障通透性的调节是一个重要而复杂的过程，涉及细胞内信号传导和紧密连接蛋白的重排。我们分析了酪氨酸磷酸酶抑制对紧密连接蛋白和内皮屏障完整性的影响，在原代细胞培养模型的基础上，猪脑毛细血管内皮细胞（PBCEC），密切模仿体外血脑屏障。酪氨酸磷酸酶抑制剂氧化苯胂（PAO）诱导增加基质金属蛋白酶（NIMP）的活性，这是由细胞-细胞接触和紧密连接蛋白occludin的蛋白水解的严重破坏。ZO-1和claudin-5不受影响。在这些条件下，跨内皮电阻（TEER）显着降低。PAO诱导的occludin蛋白水解可被不同的MMP抑制剂所阻止。过钒酸盐（PV）降低TEER类似于PAO，但不增加MMP活性。PV处理的细胞的细胞-细胞接触似乎不受影响，occludin蛋白水解没有发生。我们的研究结果表明，酪氨酸磷酸酶抑制可以影响独立的屏障性能，但也与基质金属蛋白酶。有证据表明，基质金属蛋白酶在内皮细胞紧密连接调节中的作用，特别是在血脑屏障，可能在一般的紧密连接（TJ）。(C)2003 Elsevier B. V.保留所有权利。
Tight junctions between endothelial cells of brain capillaries form the structural basis of the blood-brain barrier (BBB), which controls the exchange of molecules between blood and CNS. Regulation of cellular barrier permeability is a vital and complex process involving intracellular signalling and rearrangement of tight junction proteins. We have analysed the impact of tyrosine phosphatase inhibition on tight junction proteins and endothelial barrier integrity in a primary cell culture model based on porcine brain capillary endothelial cells (PBCEC) that closely mimics the BBB in vitro. The tyrosine phosphatase inhibitor phenylarsine oxide (PAO) induced increased matrix metalloproteinase (NIMP) activity, which was paralleled by severe disruption of cell-cell contacts and proteolysis of the tight junction protein occludin. ZO-1 and claudin-5 were not affected. Under these conditions, the transendothelial electrical resistance (TEER) was markedly reduced. PAO-induced occludin proteolysis could be prevented by different MMP inhibitors. Pervanadate (PV) reduced the TEER similar to PAO, but did not increase MMP activity. Cell-cell contacts of PV-treated cells appeared unaffected, and occludin proteolysis did not occur. Our results suggest that tyrosine phosphatase inhibition can influence barrier properties independent of, but also correlated to MMPs. Evidence is given for a role of MMPs in endothelial tight junction regulation at the BBB in particular and probably at tight junctions (TJs) in general. (C) 2003 Elsevier B.V. All rights reserved.