title: Pharmacologic Activation of Wnt Signaling by Lithium Normalizes Retinal Vasculature in a Murine Model of Familial Exudative Vitreoretinopathy.
abstract: Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies. Lrp5(-/-) mice displayed significantly delayed retinal vascular development, absence of deep layer retinal vessels, leading to increased levels of vascular endothelial growth factor and subsequent pathologic glomeruloid vessels, as well as decreased inner retinal visual function. Lithium treatment in Lrp5(-/-) mice significantly restored the delayed development of retinal vasculature and the intralaminar capillary networks, suppressed formation of pathologic glomeruloid structures, and promoted hyaloid vessel regression. Moreover, lithium treatment partially rescued inner-retinal visual function and increased retinal thickness. These protective effects of lithium were largely mediated through restoration of canonical Wnt signaling in Lrp5(-/-) retina. Lithium treatment also substantially increased vascular tubular formation in LRP5-deficient endothelial cells. These findings suggest that pharmacologic activation of Wnt signaling may help treat ocular pathologies in FEVR and potentially other defective Wnt signaling-related diseases.
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zhongxiao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Chi-Hsiu
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Favazza
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Peyton C
authors.initials: PC
authors.lastname: Morss
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Saba
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Fredrick
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: James D
authors.initials: JD
authors.lastname: Akula
authors.affiliation: Department of Ophthalmology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: jing.chen@childrens.harvard.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D012160:Retina / Q000187:drug effects / Q000196:embryology; D012164:Retinal Diseases / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012171:Retinal Vessels / Q000187:drug effects / Q000196:embryology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D008094:Lithium