title: Antiangiogenic effects of β2 -adrenergic receptor blockade in a mouse model of oxygen-induced retinopathy.
abstract: Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity. In mice with OIR, beta-adrenergic receptor (β-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 β-ARs on retinal proangiogenic factors, pathogenic neovascularization and electroretinographic responses. Our results demonstrate that β(2) -AR blockade with ICI 118,551 decreases retinal levels of proangiogenic factors and reduces pathogenic neovascularization, whereas β(1) - and β(3) -AR antagonists do not. Determination of retinal protein kinase A activity is indicative of the fact that β-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, β(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 β(2) -ARs constitutes an important part of the retinal response to hypoxia. Lastly, immunohistochemical studies demonstrate that β(2) -ARs are localized to several retinal cells, particularly to Müller cells suggesting the possibility that β(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 β(2) -AR activity and indicate that β(2) -AR blockade can be effective against retinal angiogenesis.
authors: Department of Biology, University of Pisa, Via San Zeno, Pisa, Italy.
authors: Davide
authors: D
authors: Martini
authors: Massimo Dal
authors: MD
authors: Monte
authors: Chiara
authors: C
authors: Ristori
authors: Elena
authors: E
authors: Cupisti
authors: Sara
authors: S
authors: Mei
authors: Patrizio
authors: P
authors: Fiorini
authors: Luca
authors: L
authors: Filippi
authors: Paola
authors: P
authors: Bagnoli
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001262:Atenolol / Q000627:therapeutic use; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D010100:Oxygen / Q000009:adverse effects*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011412:Propanolamines / Q000627:therapeutic use; D012333:RNA, Messenger; D034741:RNA, Small Interfering / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015861:Retinal Neovascularization / Q000188:drug therapy; D012178:Retinopathy of Prematurity / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D018709:Statistics, Nonparametric; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D020533:Angiogenesis Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011412:Propanolamines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018343:Receptors, Adrenergic, beta-2; D042461:Vascular Endothelial Growth Factor A; C026777:ICI 118551; D001262:Atenolol; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen