Bradykinin increases the permeability of the blood-tumor barrier by the caveolae-mediated transcellular pathway

Bradykinin (BK) increases the permeability of the blood-tumor barrier (BTB) selectively through the transcellular pathway; however, the role of the caveolae structural proteins caveolin-1 and caveolin-2 in this process has not been precisely elucidated. Thus, this study was performed to examine whether caveolin-1 and caveolin-2 are involved in the regulation of this biological process. In the rat brain glioma (C6) model, western blot, immunohistochemistry, and immunofluorescence assays were used to detect the expression levels and locations of caveolin-1 and caveolin-2. The results showed that caveolin-1 and caveolin-2 levels increased 5 min after BK infusion, peaked at 15 min, and then decreased. Meanwhile, Evans blue (EB) assay showed that the permeability of the BTB increased significantly after BK infusion. In our previous study we demonstrated that the quantity of pinocytotic vesicles in the endothelial cells was dramatically augmented 15 min after BK infusion. The time point at which changes of caveolin-1 and caveolin-2 reached their peak was the same as that at which EB and the quantity of pinocytotic vesicles reached their peaks. This led to the conclusion that the BK-mediated BTB permeability increase resulting from augmentation of the quantity of pinocytotic vesicles (transcellular pathway) is associated with the significantly up-regulated expression of caveolin-1 and caveolin-2. This study thus contributes further to elucidating the molecular mechanism of opening of the BTB by BK and provides a theoretical basis for clinical application of BK.