Lack of netrin-4 modulates pathologic neovascularization in the eye.

Abstract

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 O2-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization.

• Authors: Norbert Kociok, Sergio Crespo-Garcia, Yong Liang, Sabrina V Klein, Christina Nürnberg, Nadine Reichhart, Sergej Skosyrski, Eva Moritz, Anna-Karina Maier, William J Brunken, Olaf Strauß, Manuel Koch, Antonia M Joussen
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 18828 (Jan 06 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26732856 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Growth Factors
• Netrin Receptors
• Netrins
• Ntn4 protein, mouse
• RNA, Messenger
• Receptors, Cell Surface
• Unc5h2 protein, mouse
• Vascular Endothelial Growth Factor A

Topics

• Animals
• Choroidal Neovascularization (genetics, metabolism)
• Disease Models, Animal
• Eye Diseases (diagnosis, etiology, pathology)
• Gene Expression Regulation
• Mice
• Mice, Knockout
• Neovascularization, Pathologic (genetics)
• Nerve Growth Factors (deficiency, genetics, metabolism)
• Netrin Receptors
• Netrins
• Neuroglia (metabolism)
• RNA, Messenger (genetics, metabolism)
• Receptors, Cell Surface (genetics, metabolism)
• Retina (metabolism, pathology)
• Retinal Diseases (diagnosis, etiology, pathology)
• Retinal Neovascularization (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)