Document Detail

Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade.
MedLine Citation:
PMID:  20739470     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Oxygen-induced retinopathy (OIR) is a model for human retinopathy of prematurity (ROP). In OIR mice, this study determined whether blockade of β-adrenergic receptors (β-ARs) with propranolol influences retinal levels of proangiogenic factors, retinal vascularization, and blood-retinal barrier (BRB) breakdown.
METHODS: Propranolol was administered subcutaneously and picropodophyllin (PPP) intraperitoneally. Intravitreal injections of vascular endothelial growth factor (VEGF) were performed. Messengers of β-ARs, VEGF, its receptors, IGF-1 and IGF-1R were measured with quantitative RT-PCR. VEGF content was determined with ELISA. β-ARs, hypoxia-inducible factor (HIF)-1α, occludin, and albumin were measured with Western blot. Retinal localization of β3-ARs was determined by immunohistochemistry. Retinopathy was assessed by scoring fluorescein-perfused retinas, and plasma extravasation was visualized by Evans blue dye.
RESULTS: Hypoxia did not influence β-AR expression, except that it increased β3-AR protein with dense β3-AR immunoreactivity localized to engorged retinal tufts. Hypoxia upregulated VEGF, IGF-1, their receptors, and HIF-1α. Propranolol dose-dependently reduced upregulated VEGF and decreased hypoxic levels of IGF-1 mRNA and HIF-1α. Blockade of IGF-1R activity with PPP did not influence propranolol's effects on VEGF. Retinal VEGF in normoxic mice or VEGF in brain, lungs, and heart of the OIR mice were unaffected by propranolol. Propranolol ameliorated the retinopathy score, restored occludin and albumin, and reduced hypoxia-induced plasma extravasation without influencing the vascular permeability induced by intravitreal VEGF.
CONCLUSIONS: This is the first demonstration that β-AR blockade is protective against retinal angiogenesis and ameliorates BRB dysfunction in OIR. Although the relevance of these results to infant ROP is uncertain, the findings may help to establish potential pharmacologic targets based on β3-AR pharmacology.
Chiara Ristori; Luca Filippi; Massimo Dal Monte; Davide Martini; Maurizio Cammalleri; Pina Fortunato; Giancarlo la Marca; Patrizio Fiorini; Paola Bagnoli
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-01-05
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  52     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-06     Completed Date:  2011-02-07     Revised Date:  2013-01-09    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  155-70     Citation Subset:  IM    
Department of Biology, University of Pisa, Pisa, Italy.
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MeSH Terms
Adrenergic beta-Antagonists / pharmacology*
Angiogenesis Inhibitors / pharmacology*
Animals, Newborn
Blood-Retinal Barrier / drug effects
Blotting, Western
Capillary Permeability / drug effects
Disease Models, Animal*
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique, Indirect
Infant, Newborn
Injections, Intraperitoneal
Injections, Subcutaneous
Insulin-Like Growth Factor I / genetics,  metabolism
Intravitreal Injections
Mice, Inbred C57BL
Oxygen / toxicity
Podophyllotoxin / analogs & derivatives,  pharmacology
Propranolol / pharmacology*
RNA, Messenger / genetics
Receptor, IGF Type 1 / antagonists & inhibitors,  genetics,  metabolism
Receptors, Adrenergic, beta / physiology*
Retinal Neovascularization / metabolism,  prevention & control*
Retinopathy of Prematurity / metabolism,  prevention & control*
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A / administration & dosage,  metabolism
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Angiogenesis Inhibitors; 0/RNA, Messenger; 0/Receptors, Adrenergic, beta; 0/Vascular Endothelial Growth Factor A; 0/vascular endothelial growth factor A, mouse; 0F35AOI227/picropodophyllin; 518-28-5/Podophyllotoxin; 525-66-6/Propranolol; 67763-96-6/Insulin-Like Growth Factor I; 7782-44-7/Oxygen; EC, IGF Type 1

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