von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish

M.H.C. van Rooijen, E.E. Voest, I. Logister, J. Bussmann, J. Korving, F.J. van Eeden, R.H. Giles, S. Schulte-Merker

Research output: Contribution to journalArticleAcademicpeer-review


Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes human patients to the development of highly vascularized neoplasms in multiple organ systems. We show that zebrafish vhl mutants display a marked increase in blood vessel formation throughout the embryo, starting at 2 days post-fertilization. The most severe neovascularization is observed in distinct areas that overlap with high vegfa mRNA expression, including the vhl mutant brain and eye. Real-time quantitative PCR revealed increased expression of the duplicated VEGFA orthologs vegfaa and vegfab, and of vegfb and its receptors flt1, kdr and kdr-like, indicating increased vascular endothelial growth factor (Vegf) signaling in vhl mutants. Similar to VHL-associated retinal neoplasms, diabetic retinopathy and age-related macular degeneration, we show, by tetramethyl rhodamine-dextran angiography, that vascular abnormalities in the vhl(-/-) retina lead to vascular leakage, severe macular edema and retinal detachment. Significantly, vessels in the brain and eye express cxcr4a, a marker gene expressed by tumor and vascular cells in VHL-associated hemangioblastomas and renal cell carcinomas. VEGF receptor (VEGFR) tyrosine kinase inhibition (through exposure to sunitinib and 676475) blocked vhl(-/-)-induced angiogenesis in all affected tissues, demonstrating that Vegfaa, Vegfab and Vegfb are key effectors of the vhl(-/-) angiogenic phenotype through Flt1, Kdr and Kdr-like signaling. Since we show that the vhl(-/-) angiogenic phenotype shares distinct characteristics with VHL-associated vascular neoplasms, zebrafish vhl mutants provide a valuable in vivo vertebrate model to elucidate underlying mechanisms contributing to the development of these lesions. Furthermore, vhl mutant zebrafish embryos carrying blood vessel-specific transgenes represent a unique and clinically relevant model for tissue-specific, hypoxia-induced pathological angiogenesis and vascular retinopathies. Importantly, they will allow for a cost-effective, non-invasive and efficient way to screen for novel pharmacological agents and combinatorial treatments.

Original languageEnglish
Pages (from-to)343-353
Number of pages11
JournalDisease Models & Mechanisms
Issue number5-6
Publication statusPublished - 26 Mar 2010


  • Animals
  • Anoxia
  • Disease Models, Animal
  • Edema
  • Humans
  • Macula Lutea
  • Mutant Proteins
  • Mutation
  • Receptors, Vascular Endothelial Growth Factor
  • Retinal Detachment
  • Retinal Neovascularization
  • Signal Transduction
  • Tumor Suppressor Proteins
  • Zebrafish
  • Zebrafish Proteins


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