Abstract
Background:
Intravitreal neovascular diseases, as in ischemic retinopathies, are a major cause of blindness. Because inflammatory mechanisms influence vitreal neovascularization and cyclooxygenase (COX)-2 promotes tumor angiogenesis, we investigated the role of COX-2 in ischemic proliferative retinopathy.
Methods and results:
We describe here that COX-2 is induced in retinal astrocytes in human diabetic retinopathy, in the murine and rat model of ischemic proliferative retinopathy in vivo, and in hypoxic astrocytes in vitro. Specific COX-2 but not COX-1 inhibitors prevented intravitreal neovascularization, whereas prostaglandin E2, mainly via its prostaglandin E receptor 3 (EP3), exacerbated neovascularization. COX-2 inhibition induced an upregulation of thrombospondin-1 and its CD36 receptor, consistent with the observed antiangiogenic effects of COX-2 inhibition; EP3 stimulation reversed effects of COX-2 inhibitors on thrombospondin-1 and CD36.
Conclusions:
These findings point to an important role for COX-2 in ischemic proliferative retinopathy, as in diabetes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Animals
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Astrocytes / drug effects
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Astrocytes / enzymology
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Astrocytes / pathology
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CD36 Antigens / metabolism
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Cell Division / drug effects
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Cells, Cultured
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Cyclooxygenase 2
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Diabetic Retinopathy / complications
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Diabetic Retinopathy / drug therapy
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Diabetic Retinopathy / enzymology*
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Diabetic Retinopathy / pathology
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Dinoprostone / metabolism
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Disease Models, Animal
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Endothelial Growth Factors / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Ischemia / complications
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Ischemia / enzymology*
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Ischemia / pathology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism*
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Lymphokines / metabolism
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Male
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Membrane Proteins
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Mice
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Mice, Inbred C57BL
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Middle Aged
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / pathology
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Rats
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Rats, Sprague-Dawley
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Receptors, Immunologic*
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Receptors, Lipoprotein / metabolism
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Receptors, Prostaglandin E / drug effects
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Receptors, Prostaglandin E / metabolism
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Receptors, Prostaglandin E, EP3 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Receptors, Scavenger
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Retina / drug effects
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Retina / enzymology
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Retina / pathology
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Retinal Vessels / drug effects
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Retinal Vessels / pathology
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Thrombospondin 1 / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Vascular Endothelial Growth Factors
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Vitreoretinopathy, Proliferative / complications
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Vitreoretinopathy, Proliferative / drug therapy
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Vitreoretinopathy, Proliferative / enzymology*
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Vitreoretinopathy, Proliferative / pathology
Substances
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CD36 Antigens
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Endothelial Growth Factors
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Enzyme Inhibitors
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Intercellular Signaling Peptides and Proteins
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Isoenzymes
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Lymphokines
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Membrane Proteins
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PTGER3 protein, human
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PTGER4 protein, human
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Ptger3 protein, mouse
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Ptger3 protein, rat
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Ptger4 protein, mouse
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Ptger4 protein, rat
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Receptors, Immunologic
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Receptors, Lipoprotein
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Receptors, Prostaglandin E
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Receptors, Prostaglandin E, EP3 Subtype
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Receptors, Prostaglandin E, EP4 Subtype
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Receptors, Scavenger
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Thrombospondin 1
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Vascular Endothelial Growth Factor Receptor-2
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Dinoprostone