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Originally published In Press as doi:10.1167/iovs.09-3652 on June 3, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5479-5486.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3652
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The Role of PGE2 Receptor EP4 in Pathologic Ocular Angiogenesis

Susan E. Yanni,1 Joshua M. Barnett,2 Monika L. Clark,1 and John S. Penn1,2,3

From the Departments of 1Cell and Developmental Biology, 2Pharmacology, and 3Ophthalmology and Visual Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.

Corresponding author: John S. Penn, Vanderbilt Eye Institute, Vanderbilt University School of Medicine, 8000 Medical Center East, Nashville, TN 37232-8808; john.penn{at}vanderbilt.edu.

Purpose. PGE2 binds to PGE2 receptors (EP1–4). The purpose of the present study was to investigate the role of the EP4 receptor in angiogenic cell behaviors of retinal Müller cells and retinal microvascular endothelial cells (RMECs) 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 wild-type Müller cells were treated with increasing concentrations of the EP4 antagonist L-161982; VEGF production was assessed. Human RMECs (HRMECs) were treated with increasing concentrations of L-161982, and cell proliferation and tube formation were assessed. Rats subjected to OIR or LCNV were administered L-161982, and the neovascular area was measured.

Results. COX-2-null mouse Müller cells treated with increasing concentrations of PGE1-OH demonstrated a significant increase in VEGF production (P ≤ 0.0165). Wild-type mouse Müller cells treated with increasing concentrations of L-161982 demonstrated a significant decrease in VEGF production (P ≤ 0.0291). HRMECs treated with increasing concentrations of L-161982 demonstrated a significant reduction in VEGF-induced cell proliferation (P ≤ 0.0033) and tube formation (P < 0.0344). L-161982 treatment significantly reduced pathologic neovascularization in OIR (P < 0.0069) and LCNV (P ≤ 0.0329).

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






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