title: Reduced retinal neovascularization, vascular permeability, and apoptosis in ischemic retinopathy in the absence of prolyl hydroxylase-1 due to the prevention of hyperoxia-induced vascular obliteration.
abstract: OBJECTIVE
  Prolyl hydroxylases (PHDs) are oxygen sensors that stabilize hypoxia-inducible factors (HIFs) to induce proinflammatory, vasopermeability, and proapoptotic factors. These may be potential targets to reduce the complications of ischemic retinopathies.
  
  
  METHODS
  Oxygen-induced ischemic retinopathy (OIR) was generated as a model for retinopathy of prematurity (ROP) by placing 7-day-old mice in 75% oxygen for 5 days and returning them to the relative hypoxia of room air for 5 days. Neovascularization (NV) and avascular areas were assessed on retinal flat-mounts by image analysis. Blood-retinal barrier breakdown was assessed using ³H-mannitol as a tracer. Apoptosis was detected with TUNEL staining. HIF-1α and VEGF were quantified using Western blot analysis and ELISA.
  
  
  RESULTS
  PHD1-deficient mice demonstrated reduced hyperoxia-associated vascular obliteration during oxygen-induced ischemic retinopathy. This was associated with subsequent reduced avascularity, vascular leakage, and pathologic NV during the hypoxic phase, which could be accounted for by a reduced expression of HIF-1α and VEGF. Apoptosis in the retina was also reduced in PHD1-depleted mice after 2 days in hyperoxia.
  
  
  CONCLUSIONS
  PHD1 deficiency is associated with a reduction of ischemia-induced retinal NV. The regulatory mechanism in this model appears to be: PHD1 depletion prevents HIF-1α degradation in hyperoxia, which induces VEGF, thus preventing hyperoxia-related vessel loss. Without a vessel deficiency, there would not be relative hypoxia when the mice are returned to room air and there would be no need to initiate angiogenesis signaling. Blocking PHD1 may be beneficial for ischemic retinopathies and inflammatory and neurodegenerative disorders.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Huang
authors.forename: Sara
authors.initials: S
authors.lastname: Van de Veire
authors.forename: Mansi
authors.initials: M
authors.lastname: Dalal
authors.forename: Rachel
authors.initials: R
authors.lastname: Parlier
authors.forename: Richard D
authors.initials: RD
authors.lastname: Semba
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Vinores
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001813:Blood-Retinal Barrier; D015153:Blotting, Western; D002199:Capillary Permeability; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency*; D015427:Reperfusion Injury; D015861:Retinal Neovascularization / Q000201:enzymology / Q000517:prevention & control*; D012171:Retinal Vessels; D012178:Retinopathy of Prematurity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D004921:Erythropoietin; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen