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Lack of netrin-4 modulates pathologic neovascularization in the eye

Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4(−/−) mice with...

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Detalles Bibliográficos
Autores principales: Kociok, Norbert, Crespo-Garcia, Sergio, Liang, Yong, Klein, Sabrina V., Nürnberg, Christina, Reichhart, Nadine, Skosyrski, Sergej, Moritz, Eva, Maier, Anna-Karina, Brunken, William J., Strauß, Olaf, Koch, Manuel, Joussen, Antonia M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702134/
https://www.ncbi.nlm.nih.gov/pubmed/26732856
http://dx.doi.org/10.1038/srep18828
Descripción
Sumario:Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4(−/−) mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4(−/−) mice. In OIR, Ntn-4(−/−) mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4(−/−) mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Müller cells and astrocytes. Laser-induced neovascularization in Nnt-4(−/−) mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O(2)-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization.