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J. M. Kasanuki, K. M. Janisch, J. Tosi, J. J. Pak, R. J. Davis, S. H. Tsang; The Effects on Retinal Vascular Development by the Von Hippel-Lindau (vhl) Tumor Suppressor Gene. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4309.
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The von Hippel-Lindau (VHL) tumor suppressor is a component of the E3-ubiquitin ligase complex, which promotes rapid degradation of the -subunit of the hypoxia inducible factor (HIF). Highly vascularized tumors are associated with Vhl mutations, due to the increase in HIF transcription factor expression. The increase in HIF levels transcribes vascular endothelial growth factor (VEGF), which causes neoangiogensis observed in numerous Vhl mutants. While the role of Vhl plays in neoangiogenisis has been studied in the renal system, the function of Vhl has not been studied in the eye. We tested if a conditional knock-out of Vhl in the retina would cause retinal abnormalities, such a neoangiogenesis and hemangioblastomas, often seen in patients with a Vhl mutation.
Conditional inactivation of Vhl was carried out using chx10-cre transgenic and Vhlflox/flox mutant mice. All comparisons were made with age matched litter-mates and C57/B6 control mice. Paraffin sections were stained with H&E to determine retinal organization. PECAM was used as an endothelial marker to observe vascular development on retinal whole mounts and sections. HIF-1, VEGF, and VEGFR2 antibodies were employed to test the effects of Vhl removal.
PECAM staining on retinal whole mounts shows hyaloid vessels in the peripheral retina and disorganization of retinal vasculature at P28. While retinal lamination is still present, PECAM expression in mutant sections is increased. HIF-1 is undetectable in the controls, but is seen throughout the retina in mutants. VEGF and VEGFR2 histology and Immunoblotting are still in progress.
Our data indicates when Vhl function is removed in chx10 positive cells, the retinal and hyaloid vasculature are affected. Hyaloid vessels can develop, but do not regress by P10 and are still present at P28, suggesting Vhl plays a role in hyaloid regression. In addition, retinal layers can form but lack normal vascular organization. The increase in HIF-1 levels implies activation of the hypoxia and angiogenesis pathway, which is consistent with the observation of an increase in PECAM expression pattern. This suggests when Vhl activates the hypoxia and angiogenesis pathway, unregulated VEGF expression disrupts retinal vascular regression and organization.
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