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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2017

Open Access 01-12-2017 | Research

Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina

Authors: José Carlos Rivera, Baraa Noueihed, Ankush Madaan, Isabelle Lahaie, Jingyi Pan, Jaques Belik, Sylvain Chemtob

Published in: Journal of Neuroinflammation | Issue 1/2017

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Abstract

Background

Tetrahydrobiopterin (BH4) is an essential cofactor in multiple metabolic processes and plays an essential role in maintaining the inflammatory and neurovascular homeostasis. In this study, we have investigated the deleterious effects of BH4 deficiency on retinal vasculature during development.

Methods

hph-1 mice, which display deficiency in BH4 synthesis, were used to characterize the inflammatory effects and the integrity of retinal microvasculature. BH4 levels in retinas from hph-1 and wild type (WT) mice were measured by LC-MS/MS. Retinal microvascular area and microglial cells number were quantified in hph-1 and WT mice at different ages. Retinal expression of pro-inflammatory, anti-angiogenic, and neuronal-derived factors was analyzed by qPCR. BH4 supplementation was evaluated in vitro, ex-vivo, and in vivo models.

Results

Our findings demonstrated that BH4 levels in the retina from hph-1 mice were significantly lower by ~ 90% at all ages analyzed compared to WT mice. Juvenile hph-1 mice showed iris atrophy, persistent fetal vasculature, significant increase in the number of microglial cells (p < 0.01), as well as a marked degeneration of the retinal microvasculature. Retinal microvascular alterations in juvenile hph-1 mice were associated with a decreased expression in Norrin (0.2-fold) and its receptor Frizzled-4 (FZD4; 0.51-fold), as well as with an augmented expression of pro-inflammatory factors such as IL-6 (3.2-fold), NRLP-3 (4.4-fold), IL-1β (8.6-fold), and the anti-angiogenic factor thrombospondin-1 (TSP-1; 17.5-fold). We found that TSP-1 derived from activated microglial cells is a factor responsible of inducing microvascular degeneration, but BH4 supplementation markedly prevented hyperoxia-induced microglial activation in vitro and microvascular injury in an ex-vivo model of microvascular angiogenesis and an in vivo model of oxygen-induced retinopathy (OIR).

Conclusion

Our findings reveal that BH4 is a key cofactor in regulating the expression of inflammatory and anti-angiogenic factors that play an important function in the maintenance of retinal microvasculature.
Appendix
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Metadata
Title
Tetrahydrobiopterin (BH4) deficiency is associated with augmented inflammation and microvascular degeneration in the retina
Authors
José Carlos Rivera
Baraa Noueihed
Ankush Madaan
Isabelle Lahaie
Jingyi Pan
Jaques Belik
Sylvain Chemtob
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-0955-x

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