April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Frizzled-4 Is Required For Retinal Angiogenesis And Maintenance Of The Blood-Retina Barrier
Author Affiliations & Notes
  • Kim T. Paes
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Ernest Wang
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Kathy Henze
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Laura Kirkpatrick
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Peter Vogel
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • David Potter
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Dennis Rice
    Ophthalmology, Lexicon Pharmaceuticals, Inc, The Woodlands, Texas
  • Footnotes
    Commercial Relationships  Kim T. Paes, Lexicon Pharmaceuticals, Inc. (E); Ernest Wang, Lexicon Pharmaceuticals, Inc. (E); Kathy Henze, Lexicon Pharmaceuticals, Inc (E); Laura Kirkpatrick, Lexicon Pharmaceuticals, Inc. (E); Peter Vogel, Lexicon Pharmaceuticals, Inc. (E); David Potter, Lexicon Pharmaceuticals, Inc. (E); Dennis Rice, Lexicon Pharmaceuticals, Inc. (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 4867. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Kim T. Paes, Ernest Wang, Kathy Henze, Laura Kirkpatrick, Peter Vogel, David Potter, Dennis Rice; Frizzled-4 Is Required For Retinal Angiogenesis And Maintenance Of The Blood-Retina Barrier. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4867.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: : Mice deficient in the secreted protein NORRIN or its receptor FRIZZLED-4 (FZD4) exhibit incomplete vascularization of the neural retina. However, due to early retinal vascular defects in the knockout models it has not been possible to study FZD4 contribution in ocular neovascular disease. To further understand the role of this signaling pathway in physiological and pathological angiogenesis, we generated a monoclonal antibody that neutralizes FZD4 function in vivo.

Methods: : Antibodies were generated by immunizing FZD4 knockout mice with the FZD4 ectodomain. A monoclonal antibody (1.99.25) was discovered that antagonizes NORRIN-induced β-catenin accumulation in vitro. 1.99.25 and an isotype matched negative control antibody were evaluated in models of developmental retinal angiogenesis (DRA), oxygen-induced retinopathy (OIR), retinal angiomatous proliferation (RAP) and laser-induced choroidal neovascularization (CNV). We also investigated the role of FZD4 in maintaining the blood-retina barrier in normal adult mice.

Results: : Administration of 1.99.25 to wild type newborn pups recapitulated the FZD4 knockout phenotype. In the in vivo models tested, 1.99.25 inhibited both physiological and pathological angiogenesis within the retina but did not affect pathological angiogenesis in the choroid. Inhibition of FZD4 in developing vascular networks resulted in up-regulation of PLVAP, a marker of fenestrated vascular endothelium that is normally lost upon assumption of tight barrier function. In the adult neural retina, treatment with 1.99.25 reinstated PLVAP expression in the deep capillary bed and enabled passage of small and large molecules through the blood-retina barrier.

Conclusions: : These results demonstrate that FZD4 is required for physiological and pathological angiogenesis in the retina and regulation of retinal endothelial cell differentiation. Furthermore, we show that FZD4 is critical in maintaining the integrity of the mature blood-retina barrier.

Keywords: retinal neovascularization • development • proliferative vitreoretinopathy 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×