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Ulrich F. Luhmann, Freya M. Mowat, Clemens A. Lange, Yanai Duran, Robin R. Ali, Wolfgang Berger, James W. Bainbridge; Norrin Promotes Neovascularisation and Revascularisation in Retinal Ischaemia. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4864.
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Norrin activates Frizzled-4/Lrp5/Tspan-12 mediated Wnt-signalling and is involved in retinal angiogenesis. Mutations in these genes lead to a group of exudative vitreoretinopathies that exhibit disrupted ocular vascular development and ischaemia/hypoxia induced retinal fibrovascular changes. We aim to understand the spatial and temporal state of retinal oxygenation in Norrin-deficient mice during vascular development and to further characterize the role of Norrin in hypoxia-induced retinal angiogenesis.
The distribution of retinal hypoxia in Norrin-deficient (Ndph ko) mice and wildtype littermates was studied at timepoints between p5 and p26 and in oxygen induced retinopathy (OIR). We detected hypoxia by Hypoxyprobe-1TM labelling and evaluated stabilisation of hypoxia-inducible transcription factors HIF1a and HIF2a by immunohistochemistry. We visualised retinal vasculature by isolectin B4 staining and quantified the areas of vaso-obliteration, neovascularisation and hypoxia by digital image analysis of retinal flat mounts.
Despite the persistence of the hyaloid vasculature and the later remodelling of the superficial retinal vasculature, we detected a weaker central, inner retinal hypoxia and a severe peripheral hypoxia in Ndph ko mice, that were maintained until p26. In OIR, we identified comparable areas of vaso-obliteration at p12, but observed a significant higher avascular area in Ndph ko mice at p17 and p26. Interestingly, despite this larger avascular area hypoxia within this area was reduced in Ndph ko mice at p17, as was the area of preretinal neovascularisation.
These data suggest that during development neither the persistent hyaloid nor the remodelled superficial vasculature redress hypoxia in the central, inner and the far peripheral retina of Norrin-deficient mice. The significant attenuation of neovascularisation and revascularisation in OIR supports Norrin’s role as a pro-angiogenic factor during developmental and pathological angiogenesis in the retina.
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