Background/Purpose:

The Angiopoietin2 (Ang2)/TEK Tyrosine Kinase Receptor (Tie2) signalling pathway acts synergistically with VEGF/flk as critical regulators of new vessel growth, morphology and stability possibly through TNFα sensitization. The aim of this study was to assess the synovial tissue levels of VEGF, Ang2 and Tie2 in inflammatory arthritis patients and examine the effect of TNF inhibitors (TNFi) on VEGF expression and angiopoietin/Tie2 signaling. Moreover we correlated these data with changes in clinical outcomes, hypoxia and oxidative damage.

Methods:

Forty four patients with inflammatory arthritis (RA n=30 and PsA n=14) underwent needle arthroscopy. All subjects had actively inflamed knee joints and were assessed pre-TNFi treatment, with a subgroup (n=20) pre/post TNFi therapy. All patients underwent full assessment including DAS28-CRP, macroscopic vascularity/synovitis, synovial biopsy and in vivo tissue pO₂ (tpO₂) was measured using a novel LICOX probe. Immunohistology and dual-immunofluorescence were used to quantify vascular factors (VEGF, Ang2 and Tie2), cell specific markers (CD3, CD68) and markers of oxidative damage (8-oxo-dG and 4HNE). 

Results:

At baseline the mean synovial tissue pO₂ (tpO₂) level was profoundly hypoxic at 25.9 mmHg, equivalent to an ambient oxygen tension 3.4%. VEGF, Ang2 and Tie2 were expressed throughout the synovium localised in the lining layer, sub-lining and vascular regions. VEGF expression correlated with macroscopic synovitis (r=0.41, p=0.031) and vascularity (r=0.40, p=0.034). High Ang2 expression was associated with greater synovitis (r=0.56, p=0.013) and number of CD68+ cells (r=0.53, p=0.013). Tie2 expression was significantly associated with CD3+ cells (r=0.39, p=0.023) and CD68+ cells (r=0.46, p=0.010) and with high ESR and CRP (both r=0.37, p=0.047). Treatment with TNFi showed a significant reduction in expression of Tie2 (p=0.034) and Ang2 (p=0.021) and this was paralleled by an increase in tpO2 levels from mean 22.8 mmHg to 30.3 mmHg. Finally, a significant association between increased ΔVEGF, ΔAng2 and ΔTie2 with high DNA damage (Δ8-oxo-dG) and lipid peroxidation (Δ4-HNE) was demonstrated (both r>0.53, p<0.05), strongly suggesting an interplay between oxidative stress and angiogenesis in a progression of chronic inflammatory arthritis.

Conclusion:

This data suggests that the Ang2/Tie2 signalling pathways may mediate in part the downstream effects of TNF blockade. Furthermore, this is the first evidence to suggest that Ang2/Tie2 maybe directly involved in leukocyte cell influx regulation and oxidative damage within the inflamed joint.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-angiopoetin2tek-tyrosine-kinase-receptor-mediated-effect-on-leukocyte-cell-influx-and-oxidative-damage-in-inflammatory-arthritis/