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.

MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5

“…Tight junctions are composed of transmembrane proteins such as occludin, claudin and junctional adhesion molecule (JAM), cytosolic scaffold proteins such as ZO-1, ZO-1, ZO-3 and cytoskeletal proteins such as F-actin [36,37]. Several studies have revealed that opening of BTB was partially caused by down-regulation of tight junction related proteins [20,38,39]. Our results of qRT-PCR, Western blot and immunofluorescence assays showed overexpression of miR-18a could significantly downregulate mRNA and protein expressions and distributions of ZO-1, occludin and claudin-5.…”

miR‐34c Regulates the Permeability of Blood–Tumor Barrier via MAZ‐Mediated Expression Changes of ZO‐1, Occludin, and Claudin‐5

“…Meanwhile, findings of immunofluorescence staining showed consistency with data given above. Studies have shown that downregulation of tight junction related proteins partially contributed to the opening of TJ or BTB (Oshima et al, ; Blaschuk et al, ; Liu et al, ; ). So far, we have proved that miR‐34c altered the integrity and permeability of BTB by regulating expressions of ZO‐1, occludin, and claudin‐5, but not ruling out the possibility that other associated proteins and U87 cytokines or secretome (Förster et al, ; Abdullah and Bayraktutan, ) might be involved in, which might be studied in the future.…”

Role of p120 Catenin in Epac1-Induced Chronic Postsurgical Pain in Rats

“…In the early stage of acute lung injury (ALI), the increase of transmembrane permeability was earlier than that of paracellular permeability [37]. Intervention of transcellular transport might be an effective strategy to prevent pulmonary edema in ALI [38–40]. In this experiment, p120 was localized in endothelial cells (Figure 4(b)) and was colocalized with Epac1 in macrophages.…”