title: Adenosine A1 Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms.
abstract: OBJECTIVE
  We critically evaluated the role of the adenosine A1 receptor (A1R) in normal development of retinal vasculature and pathogenesis of retinopathy of prematurity (ROP) by using the A1R knockout (KO) mice and oxygen-induced retinopathy (OIR) model.
  
  
  METHODS
  Mice deficient in A1Rs and their wild-type (WT) littermates were examined during normal postnatal development or after being subjected to 75% oxygen from postnatal day (P) 7 to P12 and to room air from P12 to P17 (OIR model of ROP). Retinal vascularization was examined by whole-mount fluorescence and cross-sectional hematoxylin-eosin staining. Cellular proliferation, astrocyte and microglial activation, and tip cell function were determined by isolectin staining and immunohistochemistry. Apoptosis was determined by TUNEL assay.
  
  
  RESULTS
  Genetic deletion of the A1R did not affect normal retinal vascularization during postnatal development with indistinguishable three-layer vascularization patterns in retina between WT and A1R KO mice. In the OIR model, genetic deletion of the A1R resulted in stage-specific effects: reduced hyperoxia-induced retinal vaso-obliteration at P12, but reduced avascular area and attenuated hypoxia-induced intraretinal revascularization without affecting intravitreal neovascularization at P17 and reduced avascular areas in retina at P21. These distinct effects of A1Rs on OIR were associated with A1R control of apoptosis mainly in inner and outer nuclear layers at the vaso-obliterative phase (P12) and the growth of endothelium tip cells at the vasoproliferative phase (P17), without modification of cellular proliferation, astrocytic activation, and tissue inflammation.
  
  
  CONCLUSIONS
  Adenosine A1 receptor activity is not required for normal postnatal development of retinal vasculature but selectively controls hyperoxia-induced vaso-obliteration and hypoxia-driven revascularization by distinct cellular mechanisms.
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Shuya
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Dingjuan
authors.initials: D
authors.lastname: Zhong
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Gu
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Tang
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Wang
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Mozi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States 4Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate S.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Huo
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Institute of Molecular Medicine, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China 5Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States.
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D003430:Cross-Sectional Studies; D004195:Disease Models, Animal; D006801:Humans; D018496:Hyperoxia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D007231:Infant, Newborn; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000009:adverse effects; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D015861:Retinal Neovascularization / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D012171:Retinal Vessels / Q000502:physiology; D012178:Retinopathy of Prematurity / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
chemical_list: D043682:Receptor, Adenosine A1; D010100:Oxygen