von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish
- van Rooijen, E., Voest, E.E., Logister, I., Bussmann, J., Korving, J., van Eeden, F.J., Giles, R.H., and Schulte-Merker, S.
- Disease models & mechanisms 3(5-6): 343-353 (Journal)
- Registered Authors
- Bussmann, Jeroen, Logister, Ive, Schulte-Merker, Stefan, van Eeden, Freek, van Rooijen, Ellen
- MeSH Terms
- Disease Models, Animal
- Macula Lutea/metabolism
- Macula Lutea/pathology
- Mutant Proteins/metabolism
- Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors
- Receptors, Vascular Endothelial Growth Factor/metabolism
- Retinal Detachment/complications
- Retinal Detachment/pathology
- Retinal Neovascularization/complications*
- Retinal Neovascularization/enzymology
- Retinal Neovascularization/pathology*
- Signal Transduction
- Tumor Suppressor Proteins/genetics
- Tumor Suppressor Proteins/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 20335444 Full text @ Dis. Model. Mech.
van Rooijen, E., Voest, E.E., Logister, I., Bussmann, J., Korving, J., van Eeden, F.J., Giles, R.H., and Schulte-Merker, S. (2010) von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish. Disease models & mechanisms. 3(5-6):343-353.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes