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Abstract Number: 341

Death Receptor 3 Causes Vascular Dysfunction in a Murine Model of Rheumatoid Arthritis

Jessica O Williams1, Eddie C.Y. Wang2, Derek Lang1 and Anwen S. Williams2, 1Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, United Kingdom, 2Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: adipose tissue, Cardiovascular disease, Co-morbidities, inflammatory arthritis and macrophages

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Session Information

Title: Rheumatoid Arthritis - Animal Models

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

J. O. Williams,
None;

E. C. Y. Wang,
None;

D. Lang,
None;

A. S. Williams,
None.

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