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S. E. Yanni, J. S. Penn; The Role of COX-2 in VEGF Induction by Retinal Muller Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):51.
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Non-steroidal anti-inflammatory drugs (NSAIDs), which function to inhibit the enzymatic activity of COX, have been effective at reducing the production of retinal VEGF and retinal neovascularization in relevant models of ocular disease. For these reasons, we believe that COX-2 mediates the production of VEGF in retinal Müller cells, one of its primary sources in retinal neovascular disease. The purpose of this study is to investigate the effect of NSAIDs, COX-2 deletion, and PG administration to COX-2 null cells on VEGF induction by Müller cells.
Primary mouse Müller cells were maintained in hypoxia for 0 to 48 hours. COX-2 protein and activity were assayed by western blotting and GC-MS, respectively. VEGF protein levels were assayed by ELISA. Müller cells derived from wild-type and COX-2 null mice were maintained in either normoxic or hypoxic conditions for 24 hours, treated with celecoxib, SC-560, or a non-selective COX inhibitor, and VEGF protein levels were assayed. COX-2 null Müller cells were treated with the stable PG analogs PGE2, carbaprostacyclin (PGI2 analog), and latanoprost (PGF2 analog) for 6 hours, and VEGF protein levels were assayed.
COX-2 protein is increased 2-fold and COX-2 activity, as determined by GC-MS prostaglandin profile data, is increased between 2- and 7-fold in hypoxia. These increases precede that of VEGF, which is ~3-fold increased at the 24 hour time point. COX-2 inhibition with celecoxib leads to reduced VEGF production in both normoxia (by 66%) and hypoxia (by 80%), as does the genetic deletion of both COX-2 alleles (by approximately 80% in normoxia and hypoxia). Treating COX-2 null Müller cells with increasing concentrations (0.1 to 10 µM) of PGE2, carbaprostacyclin and latanoprost leads to a dose-dependent rescue of VEGF production in null cells.
These data demonstrate that hypoxia induces COX-2, PG production, and VEGF synthesis in Müller cells, and that both normoxic and hypoxic VEGF production is partially COX-2-dependent. Stable analogs of specific PGs rescued VEGF production in COX-2 null cells. These data suggest the presence of COX-2-dependent aspects of VEGF production in mouse retinal Müller cells.
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