September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Receptor-independent activation of Wnt Signaling protects retinal vasculature and visual function in a mouse model of familial exudative vitreoretinopathy
Author Affiliations & Notes
  • Zhongxiao Wang
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Chi-Hsiu Liu
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ye Sun
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Yan Gong
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • James D Akula
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Jing Chen
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Tara Favazza
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Nicholas Saba
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Thomas Fredrick
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Peyton Morss
    Ophthalmolopgy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Zhongxiao Wang, None; Chi-Hsiu Liu, None; Ye Sun, None; Yan Gong, None; James Akula, None; Jing Chen, None; Tara Favazza, None; Nicholas Saba, None; Thomas Fredrick, None; Peyton Morss, None
  • Footnotes
    Support  National Institute of Health/National Eye Institute (R01 EY024963)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3644. doi:
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      Zhongxiao Wang, Chi-Hsiu Liu, Ye Sun, Yan Gong, James D Akula, Jing Chen, Tara Favazza, Nicholas Saba, Thomas Fredrick, Peyton Morss; Receptor-independent activation of Wnt Signaling protects retinal vasculature and visual function in a mouse model of familial exudative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3644.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Familial exudative vitreoretinopathy (FEVR) is a rare pediatric vascular eye disease characterized by abnormal ocular vasculature and visual impairment consequent to mutations related to the Wnt signaling pathway. This study sought to investigate if activating Wnt signaling downstream of the genetic receptor-level-defects may bypass the disease mutations and rescue abnormal retinal vasculature and visual function in a mouse model of FEVR disease.

Methods : Low-density lipoprotein receptor-related protein 5 (LRP5) knockout (Lrp5-/-) mouse was employed to model FEVR. Littermate Lrp5-/- mice were intraperitoneally treated with lithium or vehicle control daily from postnatal day (P) 1. Retinas were flat-mounted and stained with isolectin to analyze vascular development at P7 and P17. Hyaloid vessels were isolated at P8 and stained with DAPI to quantify the hyaloid vessel regression. Electroretinography (ERG) and optical coherence tomographs (OCT) were performed to measure the visual function and retinal thickness. Western blotting was used to measure proteins indicative of Wnt signaling activation in the retina. Tubular formation assay was performed in vitro using human retinal microvascular endothelial cells to evaluate the effects of lithium on endothelial cell function.

Results : Lithium treatment significantly restored the otherwise underdeveloped retinal vasculature and absent intralaminar capillary networks, decreased pathologic glomeruloid vessels and promoted regression of hyaloid vessels in Lrp5-/- mice. Lithium treatment also partially rescued inner-retinal visual function, and increased retinal thickness. These protective effects were mediated through restoration of canonical Wnt signaling in Lrp5-/- retina, in vivo. Increased endothelial cell function in vascular tubular formation assay by lithium treatment was confirmed in human retinal endothelial cells with LRP5 deficiency in vitro.

Conclusions : Receptor-independent Wnt signaling activation by lithium is a promising approach to normalizing retinal vasculature in FEVR, and potentially beneficial to other diseases that are consequent to Wnt signaling deficiency.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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