title: Permeability of the blood-tumor barrier is enhanced by combining vascular endothelial growth factor with papaverine.
abstract: 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.
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors: Zhi-hang
authors: ZH
authors: Yang
authors: Li-bo
authors: LB
authors: Liu
authors: Li-ni
authors: LN
authors: Zhao
authors: Yun-hui
authors: YH
authors: Liu
authors: Yi-xue
authors: YX
authors: Xue
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000473:pathology; D007150:Immunohistochemistry; D046529:Microscopy, Electron, Transmission; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000473:pathology*; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010873:Pinocytosis / Q000187:drug effects; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions / Q000187:drug effects / Q000648:ultrastructure; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D010726:Phosphodiesterase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D010208:Papaverine
keywords: blood-tumor barrier; papaverine; pinocytotic vesicle; tight junctions; vascular endothelial growth factor