Tie2 as a novel key factor of microangiopathy in systemic sclerosisReport as inadecuate




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Arthritis Research and Therapy

, 19:105

First Online: 25 May 2017Received: 29 November 2016Accepted: 02 May 2017DOI: 10.1186-s13075-017-1304-2

Cite this article as: Moritz, F., Schniering, J., Distler, J.H.W. et al. Arthritis Res Ther 2017 19: 105. doi:10.1186-s13075-017-1304-2

Abstract

BackgroundThe angiopoietinAng-Tie2 system is a key regulator of vascular biology. The expression of membrane bound mb Tie2 and Ang-1 ensures vessel stability, whereas Ang-2, inducible by vascular endothelial growth factor VEGF, hypoxia, and inflammation, acts as an antagonist. Tie2 signalling is also attenuated by soluble Tie2 sTie2, the extracellular domain of the receptor, which is shed upon stimulation with VEGF. Herein, we investigate the role of Ang-Tie2 in the peripheral vasculopathy in systemic sclerosis SSc including animal models.

MethodsThe expression of Ang-1-2 and Tie2 in skin-serum of SSc patients was compared with healthy controls by immunohistochemistry IHC-ELISA. Expression of Ang-Tie2 was analysed in different animal models: VEGF transgenic tg mice, hypoxia model, bleomycin-induced skin fibrosis, and tight skin 1 TSK1 mice.

ResultsIn SSc, dermal microvessels abundantly expressed Ang-2, but not Ang-1 compared with healthy controls. The percentage of mbTie2+ microvessels was profoundly decreased whereas the levels of sTie2 were increased already in early disease. Both in skin and sera of SSc patients, the Ang1-2 ratio was reduced, being lowest in patients with digital ulcers indicating vessel destabilizing conditions. We next studied potential influencing factors in animal models. The VEGF tg mouse model, the hypoxia, and the inflammation-dependent bleomycin model all showed a similar dysregulation of Ang-Tie2 as in SSc, which did not apply for the non-inflammatory TSK1 model.

ConclusionPeripheral microvasculopathy in SSc results from a complex dysregulation of angiogenic signalling networks including the VEGF and the Ang-Tie2 system. The profoundly disturbed Ang-Tie-2 balance might represent an important target for vascular therapeutic approaches in SSc.

KeywordsMicrovasculopathy Systemic sclerosis Angiopoietins Tie2 Abbreviations+-Heterozygous

+-+Homozygous

AngAngiopoietin

dcDiffuse cutaneous

ECEndothelial cells

HMVECHuman microvascular endothelial cell

HPFHigh power field

IHCImmunohistochemistry

lcLimited cutaneous

mbMembrane bound

SEMStandard error of the mean

SScSystemic sclerosis

sTie2Soluble Tie2

tgTransgenic

TSK1Tight skin 1

VEGFVascular endothelial growth factor

vWFvon Willebrand factor

wtWildtype

Electronic supplementary materialThe online version of this article doi:10.1186-s13075-017-1304-2 contains supplementary material, which is available to authorized users.





Author: Falk Moritz - Janine Schniering - Jörg H. W. Distler - Renate E. Gay - Steffen Gay - Oliver Distler - Britta Maurer

Source: https://link.springer.com/







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