title: Protective effects of β1/2 adrenergic receptor deletion in a model of oxygen-induced retinopathy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dal Monte
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.affiliation: Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattei
authors.affiliation: Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital, Florence, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.affiliation: Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D012313:RNA; D010100:Oxygen
keywords: VEGF; immunoblotting; immunohistochemistry; norepinephrine