VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly

Tight junctions between brain microvessel endothelial cells (BMECs) maintai n the blood-brain barrier. Barrier breakdown is associated with brain tumor s and central nervous system diseases. Tumor cell-secreted vascular endothe lial growth factor (VEGF) increases microvasculature permeability in vivo a nd is correlated with the induction of clinically severe brain tumor edema. Here we investigated the permeability-increasing effect and tight junction formation of VEGF. By measuring [C-14] sucrose flux and transendothelial e lectrical resistance (TER) across BMEC monolayer cultures, we found that VE GF increased sucrose permeability and decreased TER. VEGF also caused a los s of occludin and ZO-1 from the endothelial cell junctions and changed the staining pattern of the cell boundary. Western blot analysis of BMEC lysate s revealed that the level of occludin but not of ZO-1 was lowered by VEGF t reatment. These results suggest that VEGF increases BMEC monolayer permeabi lity by reducing occludin expression and disrupting ZO-1 and occludin organ ization, which leads to tight junction disassembly. Occludin and ZO-1 appea r to be downstream effectors of the VEGF signaling pathway.