ArticleInvestigative ophthalmology & visual science2014
The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling.
Article in Investigative ophthalmology & visual science, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Outcomes of vitreoretinal surgery for familial exudative vitreoretinopathy: a systematic review and meta-analysis of the current literature.International ophthalmology · 2026Pooled it
- A novel variant p.Y250C of FZD4 influences Norrine/β-catenin signaling pathway that associates with familial exudative vitreoretinopathy (FEVR).Scientific reports · 2026Article
- Development of Norrin-Based Protein Therapeutic for Activation of Norrin-Wnt Signaling in Human Retinal Endothelial Cells.International journal of molecular sciences · 2025Article
- Nrf2 Deficiency in Müller Cells Exacerbates Pathological Neovascularization in Ischemic Retinopathy.Arteriosclerosis, thrombosis, and vascular biology · 2025Article
- Review
- Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice.The Journal of clinical investigation · 2023Article
- Vascular features around the optic disc in familial exudative vitreoretinopathy: findings and their relationship to disease severity.BMC ophthalmology · 2023Article
- Neurovascular abnormalities in retinopathy of prematurity and emerging therapies.Journal of molecular medicine (Berlin, Germany) · 2022Review
- Spectrum of Mutations inFrontiers in genetics · 2022Review
- Formyl Peptide Receptor 2 Alleviates Hepatic Fibrosis in Liver Cirrhosis by Vascular Remodeling.International journal of molecular sciences · 2021Article
- Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier.Science advances · 2020Article
- A mouse model for kinesin family member 11 (Kif11)-associated familial exudative vitreoretinopathy.Human molecular genetics · 2020Article
- Norrin restores blood-retinal barrier properties after vascular endothelial growth factor-induced permeability.The Journal of biological chemistry · 2020Article
- Endogenous Wnt/β-catenin signaling in Müller cells protects retinal ganglion cells from excitotoxic damage.Molecular vision · 2020Article
- Roles of HIFs and VEGF in angiogenesis in the retina and brain.The Journal of clinical investigation · 2019Article
- Cholinergic neural activity directs retinal layer-specific angiogenesis and blood retinal barrier formation.Nature communications · 2019Article
- Article
- The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming.Cell reports · 2019Article
- Wnt Signaling in vascular eye diseases.Progress in retinal and eye research · 2019Review
- Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo 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.
methodsRetinal 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 Müller glia, and (3) conditional deletion of the VEGF coreceptor neuropilin1 (NRP1) in ECs.
resultsAll three conditions reduced vascular proliferation. Eliminating HIF2-alpha in Müller 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.
conclusionsIn 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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