Abstract
BackgroundThe angiopoietin(Ang)/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.
Highlights
The angiopoietin(Ang)/Tie2 system is a key regulator of vascular biology
Moritz et al Arthritis Research & Therapy (2017) 19:105 is known about soluble Tie2, the extracellular domain of the Tie2 receptor, which is released by proteolytic cleavage by matrix metalloproteases upon stimulation with vascular endothelial growth factor (VEGF) in a process referred to as shedding [13, 14]. sTie2 is detectable in healthy individuals, and increased serum concentrations were measured in cardiovascular diseases, diabetic retinopathy [15], and systemic sclerosis (SSc) [16, 17]
Dysregulation of the Ang/Tie2 system in the dermal microvasculopathy in SSc In skin biopsies of SSc patients, the microvascular density was generally reduced compared with healthy controls (ratio of von Willebrand Factor (vWF)+ vessels/high power fields (HPF) 27.3(24,38) vs. 45.5(31,60); p = 0.001; Fig. 2a, b)
Summary
The expression of membrane bound (mb) Tie and Ang-1 ensures vessel stability, whereas Ang-2, inducible by vascular endothelial growth factor (VEGF), hypoxia, and inflammation, acts as an antagonist. Tie signalling is attenuated by soluble Tie (sTie2), the extracellular domain of the receptor, which is shed upon stimulation with VEGF. The binding of Ang-1, produced by vascular smooth muscle cells and other perivascular cells, to the membrane-bound (mb) Tie receptor on endothelial cells (EC) is crucial for vessel stability. Moritz et al Arthritis Research & Therapy (2017) 19:105 is known about soluble Tie (sTie2), the extracellular domain of the Tie receptor, which is released by proteolytic cleavage by matrix metalloproteases upon stimulation with VEGF in a process referred to as shedding [13, 14].
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