The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling.

摘要: Purpose To define the role of hypoxia and vascular endothelial growth factor (VEGF) in modifying pattern, density, permeability retinal vasculature mouse models which Norrin/Frizzled4 signaling is impaired. Methods Retinal structure was analyzed mice with mutation Ndp (the gene coding for Norrin) or Frizzle4 (Fz4) without three additional perturbations: (1) hyperoxia reduction VEGF, (2) reduced induction VEGF response to hypoxia, (3) responsiveness cells (ECs) VEGF. These perturbations were produced, respectively, by genetic ablation rod photoreceptors degeneration 1 (rd1) mutant background, conditional deletion hypoxia-inducible (HIF)-2alpha either all neural retina specifically Muller glia, coreceptor neuropilin1 (NRP1) ECs. Results All conditions proliferation. Eliminating HIF2-alpha glia blocked inner nuclear layer, identifying as transcription responsible these cells. When eliminated, a secondary elevation levels required compromise barrier transendothelial movement high molecular weight compounds. Conclusions In absence Norrin Frizzled4, phenotype determined primary defect (i.e., canonical Wnt signaling) compensatory responses resulting from hypoxia. This work may be useful guiding therapeutic strategies treatment familial exudative vitreoretinopathy (FEVR).