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Sabrina Klein, Anna-Karina Maier, Yong Liang, Norbert Kociok, Manuel Koch, William Brunken, Olaf Strauss, Antonia Joussen; Involvement of netrin-4 in oxygen induced neovascularisation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5608.
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© ARVO (1962-2015); The Authors (2016-present)
The pathological formation of blood vessels is mostly accompanied by degeneration of the neuronal tissue in the retina. Netrins are a laminin-related family of matrix-binding secreted proteins which were first documented as long ranging guidance signals in normal and pathological neuroangiogenesis. Netrin-4 is a 628 amino acid-long protein and the newest member of the netrin family. Previous studies showed that angiogenesis is inhibited through binding of netrin-4 to its receptors, but the exact role of netrin-4 in neuronal degeneration and neoangiogenesis is still not understood. Here we report developmental changes in retinal vascularisation in wild-type and netrin-4 knockout mice in a paradigm for ROP.
Wildtype and netrin-4 knockout (Ntn4-/-) mice were exposed to hyperoxia from P7 to P12 (75% O2). Control groups were kept at room air. Flatmounts of the retina were prepared at different timepoints during the retinal development starting from P6. Haematoxilin-Eosin and immunohistochemical stainings were performed on flatmounts and paraffin slides followed by image and statistical evaluation. The mean avascular area at each time point is the unvascularized numerical percentage of the whole retinal area which was statistically evaluated.
Netrin-4 deficient mice showed no obvious difference in retinal vessel development under control conditions compared to that of the wild-type mice. However, in ROP paradigm, we found at P10 a significantly increased avascular area of over 36% in Netrin-4 -/- mice compared to that in wild-type mice (29%). At later time points the re-vascularisation occurred much faster in the Netrin-4 -/- mice. While the avascular area at P17 still accounts for about 10% of the wild-type retina, the retina is fully re-vascularized at this time point in Netrin-4 -/- mice. Furthermore, in the absence of netrin-4 we observed instead of neovascular tufts pathological vessels in the superficial layer of the retina. These vessels are highly degenerated with nodistinguishable beginning and end so that a functional blood flow appears to be impossible.
Our results indicate the role of netrin-4 for re-establishment of vessels in pathological conditions. Under control conditions vessel proliferation appears to be normal. Whereas under ROP conditions netrin-4 appeared as a key-regulator blood vessel formation.
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