Permeability of the blood–tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine
Permeability of the blood–tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine
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DOI：
10.1002/jnr.23348
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发表时间：
2014-06
影响因子：
4.2
通讯作者：
Zhi-hang Yang;Libo Liu;Li-ni Zhao;Yunhui Liu;Yixue Xue
中科院分区：
文献类型：
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作者：
Zhi-hang Yang;Libo Liu;Li-ni Zhao;Yunhui Liu;Yixue Xue
本研究旨在确定血管内皮生长因子（VEGF），罂粟碱（PA），以及VEGF和PA的组合对血液肿瘤屏障（BTB）的渗透性的影响，并确定可能的分子机制。在大鼠C6胶质瘤模型中，VEGF和PA可显著增加伊文思蓝（EB）通过BTB的外渗。VEGF和PA联合输注后，VEGF诱导和PA诱导的EB外渗增加进一步增加。透射电子显微镜（TEM）显示VEGF和PA的组合不仅显着打开了紧密连接（TJ），而且显着增加了脑微血管内皮细胞（BMEC）的胞饮小泡的存在。Western blot和免疫组化结果显示，VEGF和PA联合作用可下调TJ相关蛋白occludin和claudin-5表达，上调小窝结构蛋白caveolin-1和caveolin-2表达，且较单独作用更为明显。此外，VEGF和PA输注后，放射免疫分析、蛋白质印迹和酶联免疫吸附试验（ELISA）的结果显示cGMP和蛋白激酶G-1（PKG-1）的表达水平显著增加，核因子-κB（NF-κB）p65活化。本研究表明，VEGF和PA联合使用可通过旁细胞途径（occludin和claudin-5下调）和跨细胞途径（caveolin-1和caveolin-2上调）增加BTB的通透性，cGMP/PKG/NF-κB信号通路可能参与了这一调节过程。© 2014 Wiley Periodicals，Inc.
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 C6 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.