Investigative Ophthalmology & Visual Science 2015-01-01

Protective effects of β1/2 adrenergic receptor deletion in a model of oxygen-induced retinopathy.

Massimo Dal Monte, Maurizio Cammalleri, Elisabetta Mattei, Luca Filippi, Paola Bagnoli

Index: Invest. Ophthalmol. Vis. Sci. 56(1) , 59-73, (2015)

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Abstract

β-adrenergic receptors (β-ARs) regulate angiogenesis in proliferative retinopathies. We studied the effects of β1/2-AR deletion in a model of oxygen-induced retinopathy (OIR) to confirm the role of β1- and/or β2-ARs in regulating angiogenesis and to get insights into the role of β3-ARs.Mice with β1/2-AR deletion (KO) were used. Levels of norepinephrine (NE), β3-ARs, transcription, and proangiogenic factors were evaluated. Retinas were analyzed for avascular area and neovascular tufts in the superficial plexus. Deep plexus and blood-retinal barrier (BRB) were also analyzed. Neovascularization, proangiogenic factors, protein kinase A (PKA) activity, and nitrite production were assessed after BRL 37344, a β3-AR agonist.Oxygen-induced retinopathy was characterized by NE upregulation with higher levels in wild type (WT) than in KO. Wild type and KO displayed comparable levels of β3-ARs, transcription, and proangiogenic factors, but differed in VEGF receptor (VEGFR) expression with VEGFR-1 in WT lower than in KO and VEGFR-2 in WT higher than in KO. Blood-retinal barrier dysfunction did not differ between WT and KO. Vascular abnormalities in the superficial plexus were abolished by β1/2-AR deletion, which also helped the development of the deep plexus. In both WT and KO, β3-AR agonism, acting through the nitric oxide pathway, caused enhanced neovascular responses with increased levels of VEGF.We confirm that β1- and β2-ARs play a pivotal role in retinal angiogenesis. In their presence, β3-ARs potentiate angiogenic responses, whereas, in their absence, β3-ARs sustain the angiogenic drive. These results suggest β-ARs as promising targets for therapies aimed to counteract proliferative retinopathies.Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.