期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 55, 期 12, 页码 8614-8625出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.14-15693
关键词
endothelial cell; canonical Wnt signaling; Norrie disease; familial exudative vitreoretinopathy
资金
- Howard Hughes Medical Institute
- National Eye Institute, National Institutes of Health [R01EY018673]
PURPOSE. To define the role of hypoxia and vascular endothelial growth factor (VEGF) in modifying the pattern, density, and permeability of the retinal vasculature in mouse models in which Norrin/Frizzled4 signaling is impaired. METHODS. Retinal vascular structure was analyzed in mice with mutation of Ndp (the gene coding for Norrin) or Frizzle4 (Fz4) with or without three additional perturbations: (1) retinal hyperoxia and reduction of VEGF, (2) reduced induction of VEGF in response to hypoxia, or (3) reduced responsiveness of vascular endothelial cells (ECs) to VEGF. These perturbations were produced, respectively, by (1) genetic ablation of rod photoreceptors in the retinal degeneration 1 (rd1) mutant background, (2) conditional deletion of the gene coding for hypoxia-inducible factor (HIF)-2alpha either in all neural retina cells or specifically in Muller glia, and (3) conditional deletion of the VEGF coreceptor neuropilin1 (NRP1) in ECs. RESULTS. All three conditions reduced vascular proliferation. Eliminating HIF2-alpha in Muller glia blocked VEGF induction in the inner nuclear layer, identifying HIF2-alpha as the transcription factor responsible for the hypoxia response in these cells. When Norrin/Frizzled4 signaling was eliminated, a secondary elevation in VEGF levels was required to compromise the barrier to transendothelial movement of high molecular weight compounds. CONCLUSIONS. In the absence of Norrin or Frizzled4, the vascular phenotype is determined by the primary defect in Norrin/Frizzled4 signaling (i.e., canonical Wnt signaling) and compensatory responses resulting from hypoxia. This work may be useful in guiding therapeutic strategies for the treatment of familial exudative vitreoretinopathy (FEVR).
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