VEGF Increases Paracellular Permeability in Brain Endothelial Cells via Upregulation of EphA2

ABSTRACT
Neurological disorders are associated with an increase in the permeability of human brain microvascular endothelial cells (HBMEC). Our previous findings have indicated that EphA2 could increase the permeability of HBMEC. Recent evidence has linked EphA2 and vascular endothelial growth factor (VEGF) to abnormalities in the vascular response. However, it is unclear whether EphA2 is involved in the VEGF‐induced changes in the permeability of HBMEC. Here, changes in permeability were determined by measuring transendothelial electrical resistance (TEER) and the flux of FITC‐dextran. We found that knockdown of EphA2 in HBMEC abolished the VEGF‐induced reduction in TEER and increase in flux of fluorescent dextran. Moreover, VEGF‐induced redistribution of ZO‐1 and the recruitment of detergent‐soluble occludin and claudin‐5 were also prevented. Further results showed that VEGF increased EphA2 expression in a time‐ and dose‐dependent manner, which was inhibited by a neutralizing antibody against VEGFR2 or SU1498. VEGF‐induced EphA2 expression was suppressed in the brain endothelium following treatments with the PI3K inhibitor LY294002, Akt inhibitor or transfection with the dominant‐negative PI3K mutants (Δp110). Similar results were obtained when ERK1/2 activation was inhibited by PD98059 or ERK1/2 siRNA transfection. Our data suggest that VEGF upregulates the expression of EphA2 in HBMEC through binding to VEGFR2 and subsequently activating the intrace...

Source: The Anatomical Record Part B: The New Anatomist - January 24, 2014 Category: Anatomy Authors: Ziwei Miao, Yanbin Dong, Wengang Fang, Deshu Shang, Dongxin Liu, Ke Zhang, Bo Li, Yu‐Hua Chen Tags: Full Length Article Source Type: research