Spontaneous CNV in a novel mutant mouse is associated with early VEGF-A-driven angiogenesis and late-stage focal edema, neural cell loss, and dysfunction

Norihiro Nagai, Pete Lundh von Leithner, Kanako Izumi-Nagai, Brett Hosking, Bo Chang, Ron Hurd, Peter Adamson, Anthony P. Adamis, Richard H. Foxton, Yin Shan Ng, David T. Shima

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Purpose. Characterization of a mouse model of spontaneous choroidal neovascularization (sCNV) and its effect on retinal architecture and function. Methods. The sCNV mouse phenotype was characterized by using fundus photography, fluorescein angiography, confocal scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), ERG, immunostaining, biochemistry, and electron microscopy. A role for VEGF-A signaling in sCNV was investigated by using neutralizing antibodies and a role for macrophages explored by cell-depletion studies. Results. The sCNV starts between postnatal day 10 and 15 (P10-P15), increasing in number and severity causing RPE disruption and dysfunction. Various morphological methods confirmed the choroidal origin and subretinal position of the angiogenic vessels. At approximately P25, vessels were present in the outer retina with instances of anastomosis of some sCNV lesions with the retinal vasculature. The number of CNV lesions was significantly decreased by systemic blockade of the VEGF-A pathway. Choroidal neovascularization size also was significantly modulated by reducing the number of lesion-associated macrophages. Later stages of sCNV were associated with edema, neuronal loss, and dysfunction. Conclusions. The sCNV mouse is a new model for the study of both early and late events associated with choroidal neovascularization. Pharmacological reduction in sCNV with VEGFA antagonists and an anti-inflammatory strategy suggests the model may be useful for investigating novel targets for treating human ocular neovascular disease.

Original languageEnglish
Pages (from-to)3709-3719
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number6
DOIs
Publication statusPublished - 2014 May 20
Externally publishedYes

Keywords

  • Animal models
  • Neovascularization
  • VEGF-A

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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    Nagai, N., von Leithner, P. L., Izumi-Nagai, K., Hosking, B., Chang, B., Hurd, R., Adamson, P., Adamis, A. P., Foxton, R. H., Ng, Y. S., & Shima, D. T. (2014). Spontaneous CNV in a novel mutant mouse is associated with early VEGF-A-driven angiogenesis and late-stage focal edema, neural cell loss, and dysfunction. Investigative Ophthalmology and Visual Science, 55(6), 3709-3719. https://doi.org/10.1167/iovs.14-13989