May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
PEDF's Action Inhibiting VEGF-Induced Permeability in Retinal Endothelial Cells Involves Beta-Catenin Signaling Pathway 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 2007, Vol.48, 1777. 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; PEDF's Action Inhibiting VEGF-Induced Permeability in Retinal Endothelial Cells Involves Beta-Catenin Signaling Pathway and uPAR Gene Expression. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1777. doi: https://doi.org/.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose:: To study the mechanism of pigment epithelium-derived factor (PEDF)’s inhibitory action on VEGF-induced vascular permeability. PEDF is found in many cell types including vascular endothelial cells. It has potent anti-permeability and anti-angiogenic activity, probably by blocking VEGF function. Decreased PEDF levels have been associated with microvascular hyper-permeability in retinopathy. Work in our laboratory indicates that, under diabetic conditions, PEDF levels remain higher and the blood-retinal barrier is preserved in uPAR knockout mice as compared to wild type mice. We have also shown previously that VEGF-induced endothelial-cell permeability is mediated by transcriptional activation of ß-catenin and activation of the uPA/uPAR system. Here we test the hypothesis that PEDF inhibits VEGF induced permeability by blocking ß-catenin signaling and inhibiting uPAR expression.

Methods:: Bovine retinal endothelial (BRE) cells were used for permeability assay based on changes in trans-endothelial electrical resistance (TER) in the presence or absence of VEGF and PEDF. Confocal immunofluorescence microscopy, cell fractionation and Western blot analysis were used to evaluate PEDF effects on VEGF-induced redistribution of ß-catenin from the membrane into the cytosol and nucleus. Real-time PCR was used to quantify uPAR expression in VEGF- and PEDF-treated BRE cells.

Results:: TER assays indicated that pretreatment with PEDF blocks VEGF- induced paracellular permeability increases in BRE cells. This phenomenon seemed to be dose dependent in that high concentrations of PEDF enhanced the VEGF effect. Real-time PCR analysis showed that PEDF blocks the action of VEGF in increasing uPAR expression. Confocal imaging and cell fractionation studies showed that PEDF inhibits VEGF-induced cytosolic accumulation and nuclear translocation of ß-catenin.

Conclusions:: PEDF blocks VEGF induced permeability by inhibiting ß-catenin nuclear translocation and preventing uPAR expression. Understanding the mechanism of PEDF's anti-permeability action at the intracellular signaling level is important for developing new PEDF-based strategies for treatment of retinopathy.

Keywords: growth factors/growth factor receptors • vascular cells • retina 
×
×

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.

×