Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy

• Published in: Investigative ophthalmology & visual science 2012-05, Vol.53 (6), p.2968-2977
• Main Authors: Chen, Jing, Joyal, Jean-Sebastian, Hatton, Colman J, Juan, Aimee M, Pei, Dorothy T, Hurst, Christian G, Xu, Dan, Stahl, Andreas, Hellstrom, Ann, Smith, Lois E H
• Format: Article
• Language: English
• Subjects: Administration; Administration, Oral; Adrenergic; Adrenergic beta-Antagonists - administration & dosage; Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Angiopoietin-1/genetics/metabolism; Angiopoietin-2 - genetics; Angiopoietin-2 - metabolism; Angiopoietin-2/genetics/metabolism; Animal; Animals; Animals, Newborn; Annan medicin och hälsovetenskap; beta/metabolism; Cell Proliferation; Disease Models; Disease Models, Animal; Dose-Response Relationship; Dose-Response Relationship, Drug; Drug; Drug Evaluation; Drug Evaluation, Preclinical; Endothelial Cells - drug effects; Enzyme-Linked Immunosorbent Assay; Erythropoietin - genetics; Erythropoietin - metabolism; Erythropoietin/genetics/metabolism; Gene Expression Profiling; Humans; In Vitro Techniques; Infant; Infant, Newborn; Injections; Injections, Intraperitoneal; Injections, Subcutaneous; Intraperitoneal; Mice; Newborn; Oral; Other Medical Sciences; Oxygen - toxicity; Preclinical; Propranolol - administration & dosage; Receptors; Receptors, Adrenergic, beta - metabolism; Receptors, Vascular Endothelial Growth Factor - genetics; Receptors, Vascular Endothelial Growth Factor - metabolism; Retina - cytology; Retinal Neovascularization - metabolism; Retinal Neovascularization - prevention & control; Retinal Neovascularization/metabolism/prevention & control; Retinopathy of Prematurity - metabolism; Retinopathy of Prematurity - prevention & control; Retinopathy of Prematurity/metabolism/prevention & control; Reverse Transcriptase Polymerase Chain Reaction; RNA - metabolism; Subcutaneous; Up-Regulation; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A/genetics/metabolism; Vascular Endothelial Growth Factor/genetics/metabolism
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.12-9691

Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.