May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
PGE2 Receptor EP4 Is a Potential Therapeutic Target for the Treatment of Pathological Ocular Angiogenesis
Author Affiliations & Notes
  • S. E. Yanni
    Vanderbilt University School of Medicine, Nashville, Tennessee
    Cell and Developmental Biology,
  • J. M. Barnett
    Vanderbilt University School of Medicine, Nashville, Tennessee
    Pharmacology,
  • M. L. Clark
    Vanderbilt University School of Medicine, Nashville, Tennessee
    Cell and Developmental Biology,
  • J. S. Penn
    Vanderbilt University School of Medicine, Nashville, Tennessee
    Cell and Developmental Biology,
    Ophthalmology and Visual Sciences,
  • Footnotes
    Commercial Relationships  S.E. Yanni, None; J.M. Barnett, None; M.L. Clark, None; J.S. Penn, None.
  • Footnotes
    Support  R01 EY07533-20, P30 EY08126-19, T32 EY07135-18
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3981. doi:https://doi.org/
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      S. E. Yanni, J. M. Barnett, M. L. Clark, J. S. Penn; PGE2 Receptor EP4 Is a Potential Therapeutic Target for the Treatment of Pathological Ocular Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3981. doi: https://doi.org/.

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

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Abstract

Purpose: : The COX-2 enzyme leads to the production of five bioactive lipid mediators (prostanoids). Of the prostanoids, PGE2 is most consistently increased in angiogenic human tumors. PGE2 may affect the angiogenic process by binding to one (or more) of four PGE2 receptors (EP1-4). The purpose of the present study was to investigate the role of EP4 receptor activation in VEGF production by retinal Müller cells and in VEGF-induced proliferation of retinal microvascular endothelial cells, and to assess the efficacy of an EP4 antagonist in rat models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (LCNV).

Methods: : Müller cells derived from COX-2 null mice were treated with increasing concentrations of the EP4 agonist PGE1-OH and VEGF production was assessed by ELISA. Human retinal microvascular endothelial cells (HRMEC) were treated with increasing concentrations of the EP4 antagonist L-161982 and VEGF-induced cell proliferation was assessed by BrdU incorporation. Rats were subjected to OIR or LCNV treatments and were administered L-161982. The effect of the drug on neovascularization was determined by clock-hour assessment and neovascular area (µm2), respectively.

Results: : COX-2 null mouse Müller cells treated with increasing concentrations (0.1-10 µM) of PGE1-OH demonstrated a significant increase in VEGF production (p ≤ 0.006). HRMEC treated with increasing concentrations (1-5 µM) of L-161982 demonstrated a significant reduction in VEGF-induced cell proliferation (p < 0.0001). L-161982 treatment (3.6 µM) reduced pathological blood vessel growth in OIR by 57%, and in LCNV by 32% (p < 0.05).

Conclusions: : Preliminary investigation has demonstrated that EP4 activation or inhibition influences the behaviors of two retinal cell types that are known to play roles in the pathological ocular angiogenesis characteristic of ROP and AMD. These findings suggest that the PGE2 receptor EP4 may be a valuable therapeutic target in neovascular eye disease.

Keywords: retina • eicosanoids • neovascularization 
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