Antiangiogenic effects of β2-adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy

Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta-adrenergic receptor (beta-AR) blockade with propranolol has been shown to ameliorate different aspects of retinal dysfunction in response to hypoxia. In the present study, we used the OIR model to investigate the role of distinct beta-ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that beta 2-AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas beta 1- and beta 3-AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that beta-AR blockers are indeed effective at the receptor level. In addition, the specificity of ICI 118,551 on retinal angiogenesis has been demonstrated by the finding that in mouse retinal explants, beta 2-AR silencing prevents ICI 118,551 effects on hypoxia-induced vascular endothelial growth factor accumulation. In OIR mice, ICI 118,551 is effective in increasing electroretinographic responses suggesting that activation of beta 2-ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that beta 2-ARs are localized to several retinal cells, particularly to Muller cells suggesting the possibility that beta 2-ARs play a role in regulating vascular endothelial growth factor production by these cells. The present results suggest that pathogenic angiogenesis, a key change in many hypoxic/ischemic vision-threatening retinal diseases, depends at least in part on beta 2-AR activity and indicate that beta 2-AR blockade can be effective against retinal angiogenesis.