The Role of PGE2 Receptor EP4 in Pathologic Ocular Angiogenesis

PURPOSE. PGE(2) binds to PGE(2) receptors (EP1-4). The purpose of the present study was to investigate the role of the EP4 receptor in angiogenic cell behaviors of retinal Muller 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. Muller cells derived from COX-2-null mice were treated with increasing concentrations of the EP4 agonist PGE(1)-OH, and wild-type Muller 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 Muller cells treated with increasing concentrations of PGE1-OH demonstrated a significant increase in VEGF production (P <= 0.0165). Wild-type mouse Muller 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. (Invest Ophthalmol Vis Sci. 2009;50:5479-5486) DOI: 10.1167/iovs.09-3652