Clinical issue

von Hippel-Lindau disease (VHL) is a rare, genetic multisystem disorder characterized by the abnormal growth of blood vessels and tumors. Between 60% and 80% of all patients have benign hemangioblastomas of the retina and central nervous system (CNS) that frequently cause neurological morbidity and mortality. VHL patients can also develop retinal neovascularization (also termed angiogenesis; the formation of new blood vessels), similar to diabetic retinopathy and age-related macular degeneration. Angiogenic retinopathies exhibit vascular leakage, macular edema (fluid accumulation) and detachment of the retina, and are the biggest cause of blindness in the Western world, with very limited treatment options. Unfortunately, the current models for angiogenesis do not fully recapitulate the complexity of angiogenic-related disorders. For instance, hemangioblastomas of the retina and CNS have not been found in any of the VHL mouse models.

The VHL tumor suppressor gene, VHL, is crucial for oxygen homeostasis. Its loss causes upregulation of HIF (hypoxia-inducible factor), a transcription factor with a central role in oxygen-regulated gene expression, which in turn increases the expression of hypoxia-inducible mRNAs, including those encoding vascular endothelial growth factor A (VEGFA), VEGFA receptors, and proteins involved in the HIF signaling pathway

Results

In this study, the authors show that zebrafish vhl mutants provide an in vivo model for pathological angiogenesis and vascular retinopathies. Using blood vessel-specific transgenes, they show that vhl mutants develop severe neovascularization in the brain, eye and trunk. The retinal vasculature of vhl−/− zebrafish is leaky, with severe macular edema and retinal detachment, mimicking human angiogenic retinopathies. As in humans, the zebrafish VEGFA orthologs, Vegfaa/Vegfab and Vegfb, are upregulated by loss of vhl, and are key effectors of the vhl−/− angiogenic phenotype; treatment with VEGF receptor inhibitors can block pathological angiogenesis in mutant fish.

Implications and future directions

These zebrafish vhl mutants can be used to understand the mechanisms underlying the development of vascular lesions in VHL disease, and are a unique and clinically relevant angiogenesis model, as pathological angiogenesis and vascular retinopathies can be studied non-invasively under normoxic conditions. Zebrafish vhl mutant embryos with fluorescently-labeled blood vessels are also a cost-effective and efficient model for whole organism screening of anti-angiogenic pharmacological agents and combinatorial therapies.