RESUMEN
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.
Asunto(s)
Retinopatía Diabética/enzimología , Isquemia/enzimología , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Receptores Inmunológicos , Vitreorretinopatía Proliferativa/enzimología , Adulto , Anciano , Animales , Astrocitos/efectos de los fármacos , Astrocitos/enzimología , Astrocitos/patología , Antígenos CD36/metabolismo , División Celular/efectos de los fármacos , Células Cultivadas , Ciclooxigenasa 2 , Retinopatía Diabética/complicaciones , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/patología , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Factores de Crecimiento Endotelial/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Isquemia/complicaciones , Isquemia/patología , Isoenzimas/antagonistas & inhibidores , Linfocinas/metabolismo , Masculino , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Ratas , Ratas Sprague-Dawley , Receptores de Lipoproteína/metabolismo , Receptores de Prostaglandina E/efectos de los fármacos , Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E , Subtipo EP4 de Receptores de Prostaglandina E , Receptores Depuradores , Retina/efectos de los fármacos , Retina/enzimología , Retina/patología , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/patología , Trombospondina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular , Vitreorretinopatía Proliferativa/complicaciones , Vitreorretinopatía Proliferativa/tratamiento farmacológicoRESUMEN
Neovascularization (NV) of the normally avascular cornea arises from various causes including inflammation, infection, trauma, and contact lens wear. Corneal NV, whatever the cause, impairs vision and threatens the survival of corneal allografts, thus representing a serious clinical problem for which treatment is limited. Recent interest has focused on vascular endothelial growth factor (VEGF), a key angiogenic factor whose role in corneal NV is amply documented. While experimental studies underscore the efficacy of anti-VEGF targeted agents, there exists no clear consensus on the ideal treatment for this multifaceted pathology. This review discusses the therapeutic potential of CD36, a well established anti-angiogenic receptor. We present evidence that CD36 contributes significantly to the maintenance of corneal avascularity wherein its deficiency leads to age-related corneal NV. Data further reveal that activation of CD36 substantially attenuates and induces regression of inflammatory corneal NV via concerted inhibition of VEGFA, c-Jun N terminal kinase-1, and c-Jun. In parallel studies, we demonstrate that hypoxia, a fundamental stimulus of NV, markedly elevates CD36 corneal expression in a hypoxia-inducible factor-1 and reactive oxygen species dependent manner. Collectively, our findings unveil interesting avenues for future research on the involvement of CD36 in neovascular eye disease and suggest CD36 agonists as potential therapeutic agents for the management of corneal NV, possibly in combination with anti-VEGF therapies.