VEGF increases BMEC monolayer permeability by affecting occludin expression and tight junction assembly.
Tight junctions between brain microvessel endothelial cells (BMECs) maintain the blood-brain barrier. Barrier breakdown is associated with brain tumors and central nervous system diseases. Tumor cell-secreted vascular endothelial growth factor (VEGF) increases microvasculature permeability in vivo and 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 [(14)C]sucrose flux and transendothelial electrical resistance (TER) across BMEC monolayer cultures, we found that VEGF increased sucrose permeability and decreased TER. VEGF also caused a loss of occludin and ZO-1 from the endothelial cell junctions and changed the staining pattern of the cell boundary. Western blot analysis of BMEC lysates revealed that the level of occludin but not of ZO-1 was lowered by VEGF treatment. These results suggest that VEGF increases BMEC monolayer permeability by reducing occludin expression and disrupting ZO-1 and occludin organization, which leads to tight junction disassembly. Occludin and ZO-1 appear to be downstream effectors of the VEGF signaling pathway.
Wang
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W
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047, USA.
Dentler
W L
WL
Borchardt
R T
RT
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002417:Cattle; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D017097:Electric Impedance; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008833:Microcirculation; D062793:Occludin; D013395:Sucrose / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000199:Actins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008565:Membrane Proteins; D062793:Occludin; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013395:Sucrose