title: Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy.
abstract: Retinopathy of prematurity adversely affects premature infants because of oxygen-induced damage of the immature retinal vasculature, resulting in pathological neovascularization (NV). Our pilot studies using the mouse model of oxygen-induced retinopathy (OIR) showed marked increases in angiogenic mediators, including endothelins and endothelin receptor (EDNR) A. We hypothesized that activation of the endothelin system via EDNRA plays a causal role in pathological angiogenesis and up-regulation of angiogenic mediators, including vascular endothelial growth factor A (VEGFA) in OIR. Mice were exposed to 75% oxygen from post-natal day P7 to P12, treated with either vehicle or EDNRA antagonist BQ-123 or EDNRB antagonist BQ-788 on P12, and kept at room air from P12 to P17 (ischemic phase). RT-PCR analysis revealed increased levels of EDN2 and EDNRA mRNA, and Western blot analysis revealed increased EDN2 expression during the ischemic phase. EDNRA inhibition significantly increased vessel sprouting, resulting in enhanced physiological angiogenesis and decreased pathological NV, whereas EDNRB inhibition modestly improved vascular repair. OIR triggered significant increases in VEGFA protein and mRNA for delta-like ligand 4, apelin, angiopoietin-2, and monocyte chemoattractant protein-1. BQ-123 treatment significantly reduced these alterations. EDN2 expression was localized to retinal glia and pathological NV tufts of the OIR retinas. EDN2 also induced VEGFA protein expression in cultured astrocytes. In conclusion, inhibition of the EDNRA during OIR suppresses pathological NV and promotes physiological angiogenesis.
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Vision Discovery Institute, Georgia Regents University, Augusta, Georgia; College of Allied Health Sciences, Georgia Regents University, Augusta, Georgia.
authors.forename: Chintan
authors.initials: C
authors.lastname: Patel
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Vision Discovery Institute, Georgia Regents University, Augusta, Georgia; College of Allied Health Sciences, Georgia Regents University, Augusta, Georgia.
authors.forename: S Priya
authors.initials: SP
authors.lastname: Narayanan
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Departments of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Vision Discovery Institute, Georgia Regents University, Augusta, Georgia.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, Georgia Regents University, Augusta, Georgia.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Sukumari-Ramesh
authors.affiliation: Department of Neurosurgery, Georgia Regents University, Augusta, Georgia.
authors.forename: Krishnan M
authors.initials: KM
authors.lastname: Dhandapani
authors.affiliation: Vision Discovery Institute, Georgia Regents University, Augusta, Georgia; Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, Georgia.
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: Vascular Biology Center, Georgia Regents University, Augusta, Georgia; Vision Discovery Institute, Georgia Regents University, Augusta, Georgia; Charlie Norwood VA Medical Center, Augusta, Georgia; Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia. Electronic address: rcaldwel@gru.edu.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism*; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D042461:Vascular Endothelial Growth Factor A; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)