Abstract
Abstract: :
Purpose:The cyclooxygenase enzymes (COX–1 and COX–2), and their products, the prostaglandins, have been implicated in several models of VEGF–dependent angiogenesis. Non–selective inhibitors of COX, and COX–2 selective inhibitors, have recently been found to inhibit retinal angiogenesis. COX–derived eicosanoids are also known to have roles in a wide range of biological processes, including the regulation of vascular tone, platelet aggregation, and inflammation, some of which may be of relevance in ischaemic proliferative retinopathies. We have investigated the role of each of the COX enzymes in an oxygen–induced mouse model of retinopathy using isoform–specific knockout mice. Methods:Mice lacking either the COX–1 (COX–1–/–) or COX–2 isoform (COX–2–/–) were employed in a model of oxygen–induced retinopathy, and the retinal vascular pattern at postnatal day 18 (P18) was compared to that of wild–type mice using fluorescein angiography. The percentage area of ischaemia and neovascular tufts was quantified for each of the groups. Fibrin deposition in the retinal vasculature was investigated using immunohistochemistry. Results:Quantitative analysis of fluorescein–perfused retinal angiograms at P18, revealed similar levels of neovascular tufts in hyperoxia–treated wild–type, COX–1–/– and COX–2–/– mice. However, hyperoxia–treated COX–2–/– mice had a significantly (P<0.001) increased area of retinal ischaemia (29.2 ± 1.9) over hyperoxia–treated wild–type (16.3 ± 2.7) or COX–1–/– (15.6 ± 2.6) mice. Fibrin deposition within retinal vessels was increased in hyperoxia–treated COX–2–/– mice implicating increased thrombotic events in these mice. Conclusions:Genetic disruption of a single COX isoform is not sufficient to prevent oxygen–induced retinopathy. We have identified a previously undocumented protective role for COX–2 in retinal ischaemic disease.
Keywords: eicosanoids • transgenics/knock–outs • retinal neovascularization