title: Contrasting effect of estrogen on VEGF induction under different oxygen status and its role in murine ROP.
abstract: OBJECTIVE
  It has been reported that 17beta-estradiol (E2) may enhance the proliferation of bovine retinal vascular endothelial cells (BRECs) by increasing the expression of VEGFR-2 and VEGF. The hypothesis in the current study was that estrogen may contribute to fetal vascular development and the cessation of exposure to estrogen of premature infants on birth may have an inhibitory effect on retinopathy of prematurity (ROP). Because ROP is thought to develop under relative hypoxia after exposure to high-dose oxygen, this study was conducted to investigate how estrogen modulates hypoxia-induced VEGF in BRECs and mouse ROP.
  
  
  METHODS
  Gene expression of VEGF and hypoxia-inducible factor (HIF)-1alpha were studied in BRECs, with or without E2, under normoxia and hypoxia (1% O2). A binding assay was performed to determine whether estrogen interferes with HIF-1-mediated induction of VEGF. In a mouse ROP model, effects of E2 were evaluated by avascular area, subsequent extraretinal neovascularization, and retinal expression of the VEGF gene, by administering E2 during hyperoxia (75% O2) and/or after exposure to room air.
  
  
  RESULTS
  Hypoxia-induced VEGF mRNA in BRECs was reduced dose dependently by 1 to 100 nM E2. E2 reduced hypoxia-induced binding of HIF-1 to the VEGF promoter site and reduced the HIF-1alpha mRNA level. In mouse ROP, injection of E2 during hyperoxia increased retinal VEGF mRNA and reduced the retinal avascular area at the end of hyperoxia. E2 treatment during the normoxia that followed reduced VEGF mRNA and extraretinal neovascularization. Treatment with E2 throughout both periods significantly improved retinopathy.
  
  
  CONCLUSIONS
  Estrogen may function as a significant modulator of the level of VEGF mRNA under different oxygen conditions and could serve as a prophylactic agent for ROP.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Michiko
authors.initials: M
authors.lastname: Mandai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takagi
authors.forename: Izumi
authors.initials: I
authors.lastname: Suzuma
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Suzuma
authors.forename: Shinji
authors.initials: S
authors.lastname: Koyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otani
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Oh
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Honda
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002417:Cattle; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007231:Infant, Newborn; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000378:metabolism* / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D004268:DNA-Binding Proteins; D004338:Drug Combinations; D016228:Endothelial Growth Factors; D004967:Estrogens; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013629:Tamoxifen