title: Up-regulation of VEGF by retinoic acid during hyperoxia prevents retinal neovascularization and retinopathy.
abstract: OBJECTIVE
  Retinopathy of prematurity (ROP) is directly associated with abnormal expression of retinal vascular endothelial growth factor (VEGF) in premature neonates. This study was to investigate whether the systemic administration of retinoic acid (RA) regulates retinal VEGF expression and prevents retinal neovascularization and retinopathy in the oxygen-induced retinopathy (OIR) mouse model.
  
  
  METHODS
  C57BL/6 mice were subjected to OIR by exposure to 75% oxygen from postnatal day (P) 7 to 12 of age. RA was intraperitoneally injected daily to pups from P6 to P9. Retinal whole mount staining and image analysis, immunostaining, Western blotting, quantitative RT-PCR, TUNEL assay, and electroretinography were performed to evaluate the effects of RA on VEGF expression, retinal neovascularization, and retinal neuron functions.
  
  
  RESULTS
  Systemic administration of RA in OIR mice promoted retinal VEGF mRNA and protein expression in phase I; the stabilized level of VEGF in phase I supported retinal vascular development and counteracted vaso-obliteration in OIR mice. Subsequently, the excessive generation of VEGF in phase II was attenuated; the retinal vascular leakage and apoptotic cells were significantly ameliorated. As a result, RA significantly prevented the development of hypoxia-induced retinal neovascularization and retinopathy in OIR mice and improved the functional recovery of retinal neurons downstream of photoreceptor cells as measured by focal electroretinography.
  
  
  CONCLUSIONS
  Systemic administration of RA regulates retinal VEGF expression and supports retinal vascular development in OIR mouse model. We propose that systemic administration of RA to extremely low birth weight, preterm infants during oxygen therapy could potentially be an effective therapeutic approach for the prevention of ROP.
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China.
authors.forename: Pingling
authors.initials: P
authors.lastname: Shi
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China.
authors.forename: Zhongzhong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China.
authors.forename: Yanting
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Eye Research Institute, Pediatric Retinal Research Lab, Oakland University, Rochester, Michigan, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mitton
authors.affiliation: Eye Research Institute, Pediatric Retinal Research Lab, Oakland University, Rochester, Michigan, United States.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Drenser
authors.affiliation: Henan Eye Institute and Henan Eye Hospital, Zhengzhou, Henan, China Eye Research Institute, Pediatric Retinal Research Lab, Oakland University, Rochester, Michigan, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D015153:Blotting, Western; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D018496:Hyperoxia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000627:therapeutic use*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin
keywords: IGF-1; OIR; ROP; VEGF; hypoxia; retinal neovascularization; retinoic acid