TY - JOUR
T1 - β2–adrenergic receptor antagonism attenuates CNV through inhibition of VEGF and IL-6 expression
AU - Lavine, Jeremy Arlin
AU - Farnoodian, Mitra
AU - Wang, Shoujian
AU - Darjatmoko, Soesiawati R.
AU - Wright, Lynda S.
AU - Gamm, David M.
AU - Ip, Michael S.
AU - Sorenson, Christine M.
AU - Sheibani, Nader
N1 - Funding Information:
Supported by National Institutes of Health Grants EY022883 and P30 EY016665, Environmental Protection Agency 83573701, and an unrestricted departmental award from Research to Prevent Blindness. NS is a recipient of Alice R. McPherson-Retina Research Foundation Chair. JAL is a recipient of the VitreRetinal Surgery Foundation Research Award. CMS is supported by RRF/Daniel M. Albert Chair.
Publisher Copyright:
© 2017, Association for Research in Vision and Ophthalmology Inc. All rights reserved.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - PURPOSE. The role of β–adrenergic receptor (AR) signaling in neovascular ocular diseases has recently emerged. We have previously reported that intraperitoneal propranolol inhibits choroidal neovascularization (CNV) in vivo and β2-AR blockade reduces vascular endothelial growth factor (VEGF) expression in mouse retinal pigment epithelium and choroidal endothelial cells in culture. Here we tested the hypothesis that the β2-AR regulates CNV through modulation of VEGF and inflammatory cytokine expression. METHODS. Mice were subjected to laser burns, inducing CNV, and were treated with an intravitreal β2-AR antagonist. After 3 and 5 days, total eye interleukin-6 (IL-6) and VEGF protein levels were measured, respectively. After 14 days, CNV was measured on choroidal– scleral flatmounts. The effects of β-AR signaling on VEGF and IL-6 expression were investigated in various mouse retinal and human RPE cells by using specific β-AR agonists and antagonists. RESULTS. β2–Adrenergic receptor signaling increased Vegf mRNA expression by approximately 3- to 4-fold in mouse retinal microglia and pericytes in culture. β2–Adrenergic receptor signaling upregulated IL-6 mRNA expression between 10- and 60-fold in mouse retinal microglia, pericytes, RPE, and choroidal endothelial cells in culture. Intravitreal injection of β2-AR antagonist ICI 118,551 reduced CNV by 35% and decreased IL-6 protein levels by approximately 50%. In primary human RPE cells, β2-AR activation also stimulated VEGF and IL-6 mRNA expression by 2- and 10-fold, respectively. CONCLUSIONS. Anti-VEGF therapy for CNV is highly effective; however, some patients are resistant to therapy while others undergo repeated, frequent treatments. β2–Adrenergic receptor signaling is a potential therapeutic target because of its angiogenic and inflammatory properties.
AB - PURPOSE. The role of β–adrenergic receptor (AR) signaling in neovascular ocular diseases has recently emerged. We have previously reported that intraperitoneal propranolol inhibits choroidal neovascularization (CNV) in vivo and β2-AR blockade reduces vascular endothelial growth factor (VEGF) expression in mouse retinal pigment epithelium and choroidal endothelial cells in culture. Here we tested the hypothesis that the β2-AR regulates CNV through modulation of VEGF and inflammatory cytokine expression. METHODS. Mice were subjected to laser burns, inducing CNV, and were treated with an intravitreal β2-AR antagonist. After 3 and 5 days, total eye interleukin-6 (IL-6) and VEGF protein levels were measured, respectively. After 14 days, CNV was measured on choroidal– scleral flatmounts. The effects of β-AR signaling on VEGF and IL-6 expression were investigated in various mouse retinal and human RPE cells by using specific β-AR agonists and antagonists. RESULTS. β2–Adrenergic receptor signaling increased Vegf mRNA expression by approximately 3- to 4-fold in mouse retinal microglia and pericytes in culture. β2–Adrenergic receptor signaling upregulated IL-6 mRNA expression between 10- and 60-fold in mouse retinal microglia, pericytes, RPE, and choroidal endothelial cells in culture. Intravitreal injection of β2-AR antagonist ICI 118,551 reduced CNV by 35% and decreased IL-6 protein levels by approximately 50%. In primary human RPE cells, β2-AR activation also stimulated VEGF and IL-6 mRNA expression by 2- and 10-fold, respectively. CONCLUSIONS. Anti-VEGF therapy for CNV is highly effective; however, some patients are resistant to therapy while others undergo repeated, frequent treatments. β2–Adrenergic receptor signaling is a potential therapeutic target because of its angiogenic and inflammatory properties.
KW - Adrenergic antagonists
KW - Choroidal neovascularization
KW - Interleukin-6
KW - VEGF
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U2 - 10.1167/iovs.16-20204
DO - 10.1167/iovs.16-20204
M3 - Article
C2 - 28114591
AN - SCOPUS:85010898408
VL - 58
SP - 299
EP - 308
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 1
ER -