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Permeability of the blood–tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine
Author(s) -
Yang Zhihang,
Liu Libo,
Zhao Lini,
Liu Yunhui,
Xue Yixue
Publication year - 2014
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23348
Subject(s) - occludin , caveolin 1 , downregulation and upregulation , vascular endothelial growth factor , extravasation , western blot , caveolae , vascular permeability , chemistry , tight junction , paracellular transport , endocrinology , medicine , biology , permeability (electromagnetism) , signal transduction , immunology , biochemistry , membrane , vegf receptors , gene
This study aims to determine the effects of vascular endothelial growth factor (VEGF), papaverine (PA), and the combination of VEGF and PA on the permeability of the blood–tumor barrier (BTB) and to determine possible molecular mechanisms contributing to the effects. In the rat C 6 glioma model, the extravasation of Evans blue (EB) through the BTB was increased significantly by VEGF and PA. VEGF‐induced and PA‐induced increase of EB extravasation was further increased after combining VEGF with PA infusion. Transmission electron microscopy (TEM) showed that the combination of VEGF and PA not only opened tight junctions (TJ) dramatically but increased the presence of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) significantly. Meanwhile, the downregulation of the TJ‐associated proteins occludin and claudin‐5 and the upregulation of the caveolae structure proteins caveolin‐1 and caveolin‐2 caused by the combination of VEGF and PA were observed by Western blot and immunohistochemistry, which were more remarkable than those by the two strategies separately. In addition, after VEGF and PA infusion, the results of radioimmunoassay, Western blot, and enzyme‐linked immunosorbent assay (ELISA) revealed a significant increase in expression levels of cGMP and protein kinase G‐1 (PKG‐1) and the activation of nuclear factor‐κB (NF‐κB) p65. This study demonstrates that combination of VEGF and PA can increase the permeability of the BTB by a paracellular pathway (downregulation of occludin and claudin‐5) and a transcellular pathway (upregulation of caveolin‐1 and caveolin‐2) and that the cGMP/PKG/NF‐κB signal pathway might be involved in the modulation process. © 2014 Wiley Periodicals, Inc.