May 2007
Volume 48, Issue 13
ARVO Annual Meeting Abstract  |   May 2007
Novel Receptor Tyrosine Kinase Inhibitor Blocks VEGF-Induced Retinal Endothelial-Cell Permeability and Migration
Author Affiliations & Notes
  • M. A. Behzadian
    Vascular Biology Cnt, Medical College of Georgia, Augusta, Georgia
  • X. Gu
    Alcon Research Ltd., Fort Worth, Texas
  • D. P. Bingaman
    Alcon Research Ltd., Fort Worth, Texas
  • C. Romano
    Alcon Research Ltd., Fort Worth, Texas
  • R. B. Caldwell
    Vascular Biology Cnt, Medical College of Georgia, Augusta, Georgia
  • Footnotes
    Commercial Relationships M.A. Behzadian, Medical College of Georgia, F; X. Gu, Alcon Research Ltd., E; D.P. Bingaman, Alcon Research Ltd., E; C. Romano, Alcon Research, Ltd, E; R.B. Caldwell, Medical College of Georgia, F; Alcon Research Ltd., C.
  • Footnotes
    Support NIH R01 grants NIH-EY04618, NIH-EY1176 and a Career Development Award from the Veterans Administration.
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1381. doi:
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      M. A. Behzadian, X. Gu, D. P. Bingaman, C. Romano, R. B. Caldwell; Novel Receptor Tyrosine Kinase Inhibitor Blocks VEGF-Induced Retinal Endothelial-Cell Permeability and Migration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1381.

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

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Purpose:: During diabetic macular edema, increased VEGF levels have been attributed to breakdown of the blood-retinal barrier. We hypothesize that hyperglycemia induces peri-cellular proteolytic activation by initiating uPAR gene expression and that VEGF/VEGFR2 signaling mediates this process. Consequently, we explored the inhibitory effects of a novel receptor tyrosine kinase inhibitor, AL-39324 (KDR IC50=4nM), versus dexamethasone against VEGF-induced retinal endothelial cell permeability and migration.

Methods:: Reduced barrier function in bovine retinal microvascular endothelial (BRE) cells was assessed using transendothelial electrical resistance (TER) via ECIS (Electrical Cell-substrate Impedance Sensing, Applied Biophysics, Troy, New York). In ECIS, electric current is passed through cell monolayers grown in 8-well electrode arrays, while resistance is continuously measured in each well during various treatments. Similarly, using TER, cell migration was determined in real time, as cells proceeded to cover the wounded areas on the electrode surface. Expression of uPAR was measured by quantitative RT-PCR. In all experiments, AL-39324 and dexmethasone were tested at 0.1 and 10µM, respectively; VEGF was used at 20 ng/ml.

Results:: Both AL-39324 and dexamethasone significantly and completely blocked VEGF-induced TER decreases (P<0.01 vs. VEGF-treatment alone, respectively). Moreover, the VEGF-induced endothelial cell migration was completely inhibited by AL-39324 and Dexamethasone (P<0.01 vs. VEGF-treatment alone, respectively). Gene expression studies showed that only AL-39324 significantly inhibited VEGF-induced uPAR mRNA expression.

Conclusions:: AL-39324 completely blocked both VEGF-induced vascular permeability and migration in BRE cells. These inhibitory effects were similar to results obtained with dexamethasone, however, AL-39324 was used at a 100-fold lower concentration. Moreover, AL-39324 demonstrated the unique ability to block uPAR mRNA expression induced by VEGF treatment, which may explain, in part, its anti-edematous mechanism of action.

Keywords: vascular cells • retina • signal transduction: pharmacology/physiology 

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