Background/Purpose: Increased cardiovascular (CV) risk is prevalent in several forms of inflammatory arthritides. The mechanisms that regulate CV disease during early inflammatory arthritis are ill-defined. Studies in humans and animal models identify matrix metalloproteinase 9 (MMP-9) as a potential regulator of CV pathology. Macrophages are early sentinels of both joint inflammation and vascular dysfunction. They are considered a major source of MMP-9 and can be induced in vitro to produce this metalloproteinase in response to Death Receptor 3 (DR3) signalling. Ablation of DR3 expression reduces MMP-9 levels in arthritic joint tissues during experimental arthritis. Here, for the first time, we measure DR3-dependent vascular dysfunction, associated macrophage infiltration and MMP-9 expression in vascular and perivascular adipose tissues (PVAT) with a view to understanding DR3’s role in initiating early CV damage during inflammatory arthritis.
Methods: Murine collagen-induced arthritis (mCIA) was induced in DBA/1 mice (WT). Constriction responses to serotonin (5HT) were used to assess vascular function in isolated sections of thoracic aorta (±PVAT) in non-mCIA and mCIA mice with mild disease. DR3-dependent changes in vascular function were analysed using age-matched DBA/1 DR3 deficient mice (DR3^-/-). Region specific (thoracic aorta and PVAT) leukocyte infiltration was determined using haematoxylin and eosin staining, whilst localisation of F4/80⁺ macrophages were visualised and MMP-9 expression quantified after immunohistochemical staining.
Results: The onset of mild arthritis was associated with inflammatory changes in the aortic vessel wall, characterised by increased macrophage infiltration (p<0.05) and DR3 expression (p<0.001). Total MMP-9 expression was unaltered (non-mCIA vs. mCIA mice). Macrophages (F4/80+), DR3 and total MMP-9 expression were all significantly elevated in PVAT (p<0.05 for all). The mCIA vascular tissues (±PVAT) exhibited significant contractile dysfunction compared to non-mCIA controls (p<0.001). The presence of PVAT was associated with a significant (p<0.001) dextral shift in constriction response curves but had no effect on maximal constriction. In DR3^-/- non-mCIA mice, leukocyte infiltration (p<0.05) and total MMP-9 (p<0.01) levels were increased in PVAT but not in the aortic vessel wall. Vascular function was unaltered (WT versus DR3^-/-) and PVAT retained its ability to shift the constriction response curve to the right (p<0.001) in both genotypes. mCIA had no impact on the leukocyte ingress or MMP-9 production in the aortic vessel wall or PVAT (WT versus DR3^-/-). However, loss of DR3 further impaired vascular function (±PVAT) in comparison to WT (p>0.001).
Conclusion: The onset of mCIA drives an inflammatory response in the PVAT; associated with macrophage infiltration, increased expression of DR3 and MMP-9, and is detrimental to vascular function.  Loss of DR3 perpetuates vascular dysfunction independently of leukocyte ingress and MMP-9 production. Further studies are justified to deduce the impact of DR3 on vascular function, in particular, the potential link with cardiovascular co-morbidities allied to arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/death-receptor-3-causes-vascular-dysfunction-in-a-murine-model-of-rheumatoid-arthritis/