Preterm birth results in abnormal foveal vascularisation, a failure of the inner retinal neurons to migrate away from the fovea, and an elevated outer nuclear layer ratio. The spatial coincidence of inner retinal and vascular abnormalities in preterm children supports the hypothesis that aspects of foveal development are interdependent.
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.
The severe ROP group progressed rapidly toward myopia, particularly during the first 1.3 years; anisometropia and astigmatism also increased with age. The mild/no ROP group showed little change in refraction. Infants treated with laser photocoagulation for severe ROP should be monitored with periodic cycloplegic refractions and provided with early optical correction.
Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, reduce the production of retinal VEGF and neovascularization in relevant models of ocular disease. We hypothesized that COX-2 mediates VEGF production in retinal Müller cells, one of its primary sources in retinal neovascular disease. The purpose of this study was to determine the role of COX-2 and its products in VEGF expression and secretion. These studies have more clearly defined the role of COX-2 and COX-2-derived prostanoids in retinal angiogenesis.
Müller cells derived from wild-type and COX-2 null mice were exposed to hypoxia for 0–24 hours. COX-2 protein and activity were assessed by western blot analysis and GC-MS, respectively. VEGF production was assessed by ELISA. Wild-type mouse Müller cells were treated with vehicle (0.1% DMSO), 10 µM PGE2, or PGE2 + 5 µM H-89 (a PKA inhibitor), for 12 hours. VEGF production was assessed by ELISA.
Hypoxia significantly increased COX-2 protein (p ≤ 0.05) and activity (p ≤ 0.05), and VEGF production (p ≤ 0.0003). COX-2 null Müller cells produced significantly less VEGF in response to hypoxia (p ≤ 0.05). Of the prostanoids, PGE2 was significantly increased by hypoxia (p ≤ 0.02). Exogenous PGE2 significantly increased VEGF production by Müller cells (p ≤ 0.0039), and this effect was inhibited by H-89 (p ≤ 0.055).
These data demonstrate that hypoxia induces COX-2, prostanoid production, and VEGF synthesis in Müller cells, and that VEGF production is at least partially COX-2-dependent. Our study suggests that PGE2, signaling through the EP2 and/or EP4 receptor and PKA, mediates the VEGF response of Müller cells.
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