title: Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy.
abstract: Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso-obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ngo
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Borowska-Fielding
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Ophthalmology and Visual Sciences, Dalhousie University and the IWK Health Centre, Halifax, NS, Canada.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Heathcote
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Nejat
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.|Department of Ophthalmology and Visual Sciences, Dalhousie University and the IWK Health Centre, Halifax, NS, Canada.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Kelly
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McMaster
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, NS, Canada.|Department of Ophthalmology and Visual Sciences, Dalhousie University and the IWK Health Centre, Halifax, NS, Canada.
authors.forename: Johane M
authors.initials: JM
authors.lastname: Robitaille
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D057895:Haploinsufficiency; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009900:Optic Nerve / Q000098:blood supply; D010100:Oxygen / Q000633:toxicity*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization; D012171:Retinal Vessels / Q000254:growth & development / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000209:etiology* / Q000235:genetics
chemical_list: D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D010100:Oxygen