Tight junctions (TJ) between retinal pigmentedepithelial (RPE) and retinal endothelial cells maintain theouter and inner blood-retinal barrier, and the breakdown ofthese barriers is associated with retinal diseases. Vascularendothelial growth factor (VEGF) increases vascular permeabilityand is thought to be involved in age-relatedmaculopathy. However, to date, little is known about theeffect of VEGF on RPE cell junctions. We have investigatedthe effect of VEGF on TJ formation by examiningtwo essential proteins, ZO-1α+ and ZO-1α−. Culturedvascular endothelial cells in the presence of 5 ng/ml VEGFsignificantly down-regulate ZO-1α+ and ZO-1α− transcriptsand proteins with significant loss of their trans-epithelialresistance (TER). Immunoconfocal analysis with an anti-ZO-1 antibody has confirmed the relocation of ZO-1 proteinfrom membrane to cytoplasm. By contrast, in thepresence of 5 ng/ml VEGF, cultured RPE cells (ARPE19and RPE51) significantly up-regulate ZO-1α+ and ZO-1α−transcripts and proteins resulting in a significant increase intheir TER. Subsequent immunoconfocal analysis has demonstratedincreased ZO-1 membrane assembly in VEGFtreatedRPE cells. Thus, VEGF has a dual capability withrespect to the regulation of the expression of some TJ proteinsat the transcriptional and post-translational levelsdepending on cell type.