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Jeremy Lavine, Shoujian Wang, SOESIAWATI DARJATMOKO, Lynda S Wright, David M Gamm, Michael S Ip, Nader Sheibani; beta2-Adrenergic receptor antagonism attenuates CNV through Inhibition of VEGF and IL-6 expression. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4995.
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© ARVO (1962-2015); The Authors (2016-present)
The role of beta-adrenergic signaling in neovascular retinal and choroidal disease has recently emerged. We previously reported that propranolol inhibits choroidal neovascularization (CNV) in vivo and beta2-adrenoreceptor blockade reduces vascular endothelial growth factor (VEGF) expression in vitro. Here we tested the hypothesis that beta2-adrenergic receptors regulate CNV in vivo, investigated the role of beta2-adrenoreceptors in inflammatory signaling, and extended these results into primary human cells.
Mice were subjected to laser burns, inducing CNV, and were treated with a single intravitreal dose of beta2-adrenoreceptor antagonist (ICI 118,551). After 14 days, neovascularization was measured on choroidal-scleral flatmounts using intercellular adhesion molecule-2 immunofluorescence staining. The effect of beta-adrenoreceptor signaling on the expression of VEGF and interleukin 6 (IL-6) was investigated in primary mouse choroidal endothelial cells, retinal pigment epithelial (RPE) cells, microglia cells, and human fetal RPE cells using specific beta-adrenoreceptor agonists and antagonists.
Intravitreal injection of ICI 118,551 reduced CNV by 40% compared to vehicle control (N=30, p<0.01). In primary mouse microglia cells, norepinephrine and the beta2-specific adrenoreceptor agonist formoterol increased Vegf mRNA expression 4-fold, while propranolol and ICI 118,551 prevented norepinephrine-stimulated Vegf mRNA expression. In primary mouse microglia, RPE, and choroidal endothelial cells, norepinephrine elevated IL-6 mRNA expression 9-fold, 24-fold, and 12-fold, respectively. This effect was completely inhibited by both propranolol and ICI 118,551 in all cell types. In primary human fetal RPE cells, norepinephrine and formoterol increased Vegf mRNA expression 2-fold.
beta2-adrenergic receptor antagonism reduces laser-induced CNV in vivo and decreases Vegf and IL-6 mRNA expression in vitro. Anti-VEGF therapy for CNV is effective for most patients; however, some patients are resistant to therapy while other patients undergo a significant burden of repeated treatments and high cost. The beta2-adrenoreceptor is a potential therapeutic target for CNV lesions because of its combined anti-angiogenic and anti-inflammatory properties.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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