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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Ependymoglial Cells / drug effects
  • Ependymoglial Cells / metabolism
  • Eye Proteins / pharmacology
  • Eye Proteins / physiology*
  • Humans
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / pharmacology
  • Nerve Tissue Proteins / physiology*
  • Oxygen / adverse effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Retinal Neovascularization / etiology
  • Retinal Neovascularization / metabolism*
  • Wnt Signaling Pathway / physiology

Substances

  • Eye Proteins
  • Ndph protein, mouse
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Oxygen