May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
P38 Map Kinase Mediates the Anti-Permeability Function of PEDF by Blocking VEGF-Induced GSK/Beta-Catenin Signaling and uPAR Gene Expression
Author Affiliations & Notes
  • J. Yang
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia
  • E. Duh
    Johns Hopkins University, Baltimore, Maryland
  • R. B. Caldwell
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia
  • M. A. Behzadian
    Vascular Biology Center, Medical College of Georgia, Augusta, Georgia
  • Footnotes
    Commercial Relationships  J. Yang, None; E. Duh, None; R.B. Caldwell, None; M.A. Behzadian, None.
  • Footnotes
    Support  NIH RO1EY04618; NIH RO1EY11766; Veterans Administration
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3972. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      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. doi: https://doi.org/.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: signal transduction • growth factors/growth factor receptors • vascular endothelial growth factor 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×