Genetic deletion of COX-2 diminishes VEGF production in mouse retinal Müller cells.

Yanni SE, McCollum GW, Penn JS
Exp Eye Res. 2010 91 (1): 34-41

PMID: 20398651 · PMCID: PMC2879458 · DOI:10.1016/j.exer.2010.03.019

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 h. 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 microM PGE(2), or PGE(2) + 5 microM H-89 (a PKA inhibitor), for 12 h. 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, PGE(2) was significantly increased by hypoxia (p < 0.02). Exogenous PGE(2) 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 PGE(2), signaling through the EP(2) and/or EP(4) receptor and PKA, mediates the VEGF response of Müller cells.

Copyright 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (21)

Animals Animals, Newborn Blotting, Western Cells, Cultured Cyclic AMP-Dependent Protein Kinases Cyclooxygenase 2 Dinoprostone Enzyme-Linked Immunosorbent Assay Gas Chromatography-Mass Spectrometry Gene Deletion Hypoxia Isoquinolines Mice Mice, Inbred C57BL Mice, Knockout Microglia Prostaglandins Protein Kinase Inhibitors Retinal Neurons Sulfonamides Vascular Endothelial Growth Factor A

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