title: β2-Adrenergic Receptor Antagonism Attenuates CNV Through Inhibition of VEGF and IL-6 Expression.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Lavine
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Mitra
authors.initials: M
authors.lastname: Farnoodian
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Shoujian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Soesiawati R
authors.initials: SR
authors.lastname: Darjatmoko
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Lynda S
authors.initials: LS
authors.lastname: Wright
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States 2McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Gamm
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States 2McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Ip
authors.affiliation: McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Sorenson
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States 2McPherson Eye Research Institute, University of Wisconsin, Madison, Wisconsin, United States.
authors.forename: Nader
authors.initials: N
authors.lastname: Sheibani
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002829:Choroid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000319:Adrenergic beta-Antagonists; D015850:Interleukin-6; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors