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J. Yang, E. Duh, R. B. Caldwell, M. A. Behzadian; P38 Map Kinase Mediates the Anti-Permeability Function of PEDF by Blocking VEGF-Induced GSK/Beta-Catenin Signaling and uPAR Gene Expression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3972.
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To understand the mechanism by which pigment epithelium-derived factor (PEDF) blocks VEGF-induced increases in vascular permeability. PEDF shows anti-permeability and anti-angiogenic activity, probably by blocking VEGF effects on vascular endothelial cells, but the molecular mechanism of its action is unknown. We have previously shown that VEGF-induced endothelial-cell permeability is mediated by transcriptional activation of β-catenin and expression of uPAR. Here, we present data showing that P38 MAP kinase acts upstream of the GSK/beta catenin pathway and that inhibition of this kinase by PEDF, blocks VEGF-induced uPAR expression and endothelial cell permeability.
Bovine retinal endothelial (BRE) cells were used for studies of paracellular permeability in the presence and absence of VEGF, PEDF and various kinase inhibitors. Western blotting and confocal microscopy were used to show cellular redistribution of β-catenin and real-time PCR was used to quantify uPAR expression.
Pretreatment of BRE cells with PEDF or with inhibitors of P38 MAPK (SB202190) blocked VEGF-induced phosphorylation of GSK, redistribution of beta-catenin and expression of uPAR. Blockade of P38 MAPK activity by MEK inhibitors (PD98059 and U0126) abrogated all downstream signaling events and also blocked the permeability increases induced by VEGF.
PEDF prevents VEGF-induced permeability by blocking P38 MAPK activity and phosphorylation/deactivation of GSK. In the active form, GSK facilitates ubiquitination/degradation of β-catenin, preventing transcriptional activation of β-catenin and expression of uPAR. Understanding the mechanism of PEDF's anti-permeability action at the intracellular signaling level is important for developing new PEDF-based targets for treatment of retinal disease.
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