title: Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy.
abstract: OBJECTIVE
  To investigate whether EphrinB2 (EfnB2) or EphB4 influence retinal angiogenesis under physiological or pathological conditions.
  
  
  METHODS
  Using the mouse model of oxygen-induced proliferative retinopathy (OIR), the expression of EfnB2, EphB4, vascular endothelial growth factor (VEGF), VEGFR1 and VEGFR2 was quantified by quantitative polymerase chain reaction (qPCR) and localized in EfnB2- and EphB4-lacZ mice. Angioproliferative retinopathy was manipulated by intravitreal injection of dimeric EfnB2 and monomeric or dimeric EphB4.
  
  
  RESULTS
  Dimeric EphB4 (EphB4-Fc) and EfnB2 (EfnB2-Fc) enhanced hypoxia-induced angioproliferative retinopathy but not physiological angiogenesis. Monomeric EphB4 (sEphB4) reduced angiogenesis. The messenger RNA (mRNA) level of EfnB2 increased significantly in the hyperoxic phase (P7-P12), while EphB4, VEGF, VEGFR1 and VEGFR2 showed a significant - up to fivefold - increased expression at P14, the start of morphologically visible vasoproliferation caused by relative hypoxia.
  
  
  CONCLUSIONS
  The ephrin/Eph system is involved in angioproliferative retinopathy. Stimulation of EphB4 and EfnB2 signalling using EfnB2-Fc and EphB4-Fc, respectively, enhanced hypoxia-induced angiogenesis. In contrast, sEphB4 inhibited hypoxia-induced angiogenesis. Therefore, angiogenesis is enhanced by signalling through both EphB4 (forward) and EfnB2 (reverse). The distinction in the expression kinetics of EphB4 and EfnB2 indicates that they govern two different signalling pathways and are regulated in diverse ways. sEphB4 might be a useful drug for antiangiogenic therapy.
authors.affiliation: University Eye Hospital, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Ehlken
authors.forename: Gottfried
authors.initials: G
authors.lastname: Martin
authors.forename: Clemens
authors.initials: C
authors.lastname: Lange
authors.forename: Eleni G
authors.initials: EG
authors.lastname: Gogaki
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fiedler
authors.forename: Florence
authors.initials: F
authors.lastname: Schaffner
authors.forename: Lutz L
authors.initials: LL
authors.lastname: Hansen
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Hansjürgen T
authors.initials: HT
authors.lastname: Agostini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003911:Dextrans; D004195:Disease Models, Animal; D036388:Ephrin-B2 / Q000008:administration & dosage / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives; D006801:Humans; D007231:Infant, Newborn; D058449:Intravitreal Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000633:toxicity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D036224:Receptor, EphB4 / Q000008:administration & dosage / Q000378:metabolism; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D012171:Retinal Vessels / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D003911:Dextrans; D036388:Ephrin-B2; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C015219:fluorescein isothiocyanate dextran; C086681:Ephb4 protein, mouse; D036224:Receptor, EphB4; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D016650:Fluorescein-5-isothiocyanate; D010100:Oxygen