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Exp Eye Res. 2016 Apr;145:317-326. doi: 10.1016/j.exer.2015.12.001. Epub 2015 Dec 17.

Norrin mediates angiogenic properties via the induction of insulin-like growth factor-1.

Author information

1
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany.
2
Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
3
Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany. Electronic address: andreas.ohlmann@ur.de.

Abstract

Norrin is an angiogenic signaling molecule that activates canonical Wnt/β-catenin signaling, and is involved in capillary formation in retina and brain. Moreover, Norrin induces vascular repair following an oxygen-induced retinopathy (OIR), the model of retinopathy of prematurity in mice. Since insulin-like growth factor (IGF)-1 is a very potent angiogenic molecule, we investigated if IGF-1 is a downstream mediator of Norrin's angiogenic properties. In retinae of transgenic mice with an ocular overexpression of Norrin (βB1-Norrin), we found at postnatal day (P)11 a significant increase of IGF-1 mRNA compared to wild-type littermates. In addition, after treatment of cultured Müller cells or dermal microvascular endothelial cells with Norrin we observed an increase of IGF-1 and its mRNA, an effect that could be blocked with DKK-1, an inhibitor of Wnt/β-catenin signaling. When OIR was induced, the expression of IGF-1 was significantly suppressed in both transgenic βB1-Norrin mice and wild-type littermates when compared to wild-type animals that were housed in room air. Furthermore, at P13, one day after the mice had returned to normoxic conditions, IGF-1 levels were significantly higher in transgenic mice compared to wild-type littermates. Finally, after intravitreal injections of inhibitory α-IGF-1 antibodies at P12 or at P12 and P14, the Norrin-mediated vascular repair was significantly attenuated. We conclude that Norrin induces the expression of IGF-1 via an activation of the Wnt/β-catenin signaling pathway, an effect that significantly contributes to the protective effects of Norrin against an OIR.

KEYWORDS:

Angiogenesis; IGF-1; Norrin; Oxygen-induced retinopathy; Retinopathy of prematurity; Wnt signaling; β-catenin

PMID:
26706283
DOI:
10.1016/j.exer.2015.12.001
[Indexed for MEDLINE]

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