title: Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis.
abstract: OBJECTIVE
  Loss-of-function mutations in hemojuvelin (HJV) cause juvenile hemochromatosis, an iron-overload disease. Deletion of Hjv in mice results in excessive iron accumulation and morphologic changes in the retina. Here, we studied the retinal vasculature in Hjv(-/-) mice.
  
  
  METHODS
  Age-matched wild-type and Hjv(-/-) mice were used for fluorescein angiography and preparation of retinal cryosections, flat-mounts, and trypsin-digested blood vessels. Retinal angiogenesis was monitored by immunofluorescent detection of isolectin-B4, endoglin, and VEGF. Retinal vasculogenesis was monitored by immunofluorescent detection of collagen IV. Reactive gliosis was assessed based on the expression of glial fibrillary acidic protein and vimentin and CD11b/c as markers for Müller cells and microglia.
  
  
  RESULTS
  Between 18 and 24 months of age, retinas of Hjv(-/-) mice displayed marked disruptions in angiogenesis and vasculogenesis. Blood vessels in Hjv(-/-) mice were tortuous and dilated, with a decrease in the tight-junction protein occludin. There was also evidence of neovascularization in Hjv(-/-) mice with blood vessels appearing in the vitreous, which were leaky. There was reactive gliosis in these mice involving both Müller cells and microglia. Such changes were not detected at 2 weeks of age. Even at the age of 4 months, retinas of Hjv(-/-) mice were almost normal with changes just beginning to appear. Thus, the vascular changes in Hjv(-/-) mouse retinas represent an age-dependent phenomenon.
  
  
  CONCLUSIONS
  Deletion of Hjv in mice leads to abnormal retinal angiogenesis/vasculogenesis, with proliferation of new, leaky blood vessels in the vitreous. These changes are accompanied with reactive gliosis involving Müller cells and microglia.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors.forename: Amany
authors.initials: A
authors.lastname: Tawfik
authors.affiliation: James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: James & Jean Culver Vision Discovery Institute, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D058851:GPI-Linked Proteins; D017353:Gene Deletion; D005911:Gliosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000071020:Hemochromatosis Protein; D007501:Iron / Q000378:metabolism*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D012160:Retina / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology*
chemical_list: D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D004247:DNA; D007501:Iron
keywords: angiogenesis; gliosis; iron; retinal vasculature