Massimo Dal Monte1, Maurizio Cammalleri1, Elisabetta Mattei2, Luca Filippi3, Paola Bagnoli1. 1. Department of Biology, University of Pisa, Pisa, Italy. 2. Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy IRCCS Fondazione Santa Lucia, Rome, Italy. 3. Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: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. RESULTS: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. CONCLUSIONS: 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.
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