The first two authors contributed equally to this work.
Bradykinin increases blood–tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton
Article first published online: 8 JAN 2008
Copyright © 2008 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 86, Issue 5, pages 1153–1168, April 2008
How to Cite
Liu, L.-b., Xue, Y.-x., Liu, Y.-h. and Wang, Y.-b. (2008), Bradykinin increases blood–tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J. Neurosci. Res., 86: 1153–1168. doi: 10.1002/jnr.21558
- Issue published online: 12 MAR 2008
- Article first published online: 8 JAN 2008
- Manuscript Accepted: 22 AUG 2007
- Manuscript Revised: 7 AUG 2007
- Manuscript Received: 18 JUL 2007
- Natural Science Foundation of China. Grant Numbers: 30670723, 30570650, 30400145
- Natural Science Foundation of Liaoning Province. Grant Number: 20052102
- Special fund for scientific research of doctor-degree subjects in colleges and universities. Grant Number: 20050159005
- blood–tumor barrier;
- tight junction;
Bradykinin (BK) has been shown to open blood-tumor barrier (BTB) selectively and to increase permeability of the BTB transiently, but the mechanism is unclear. This study was performed to determine whether BK opens the BTB by affecting the tight junction (TJ)-associated proteins zonula occluden-1 (ZO-1), occludin, and caludin-5 and cytoskeleton protein filamentous actin (F-actin). In rat brain glioma model and BTB model in vitro, we find that the protein expression levels of ZO-1, occludin, and claudin-5 are attenuated by BK induction. Immunohistochemistry and immunofluorescence assays show that the attenuated expression of ZO-1, occludin, and claudin-5 and F-actin is most obvious in the smaller tumor capillaries (<20 μm) after BK infusion, and there is no change in the larger tumor capillaries (>20 μm). The redistribution of ZO-1, occludin, and claudin-5 and rearrangement of F-actin in brain microvascular endothelial cells are observed at the same time. Meanwhile, Evans blue assay shows that the permeability of BTB increases after BK infusion. Transmission electron microscopy indicates that TJ is opened and that pinocytotic vesicular density is increased. Transendothelial electrical resistance (TEER) and horseradish peroxidase flux assays also reveal that TJ is opened by BK induction. In addition, radioimmunity and Western blot assay reveal a significant decrease in expression levels of cAMP and catalytic subunit of protien kinase A (PKAcs) of tumor tissue. This study demonstrates that the increase of BK-mediated BTB permeability is associated with the down-regulation of ZO-1, occludin, and claudin-5 and the rearrangement of F-actin and that cAMP/PKA signal transduction system might be involved in the modulating process. © 2008 Wiley-Liss, Inc.