Characterization of death receptor 3‐dependent aortic changes during inflammatory arthritis

Murine collagen‐induced arthritis ( mCIA ) is characterized by decreased vascular constriction responses and increased MMP ‐9. Here, we describe additional histological alterations within the aorta and surrounding perivascular adipose tissue ( PVAT ), study the role of PVAT in constriction response, and investigate the potential involvement of death receptor 3 ( DR 3). mCIA was induced in wild‐type ( WT ) and DR 3 −/− mice with nonimmunized, age‐matched controls. Vascular function was determined in isolated aortic rings ± PVAT , using isometric tension myography, in response to cumulative serotonin concentrations. Cellular expression of F4/80 (macrophages), Ly6G (neutrophils), DR 3, and MMP ‐9 was determined using immunohistochemistry. In WT s, arthritis‐induced vascular dysfunction was associated with increased F4/80+ macrophages and increased DR 3 expression in the aorta and PVAT . MMP ‐9 was also up‐regulated in PVAT , but did not correlate with alterations of PVAT intact constriction. DR 3 −/− mice inherently showed increased leukocyte numbers and MMP ‐9 expression in the PVAT , but retained the same nonarthritic constriction response as DR 3 WT mice ± PVAT . Arthritic DR 3 −/− mice had a worsened constriction response than DR 3 WT and showed an influx of neutrophils to the aorta and PVAT . Macrophage numbers were also up‐regulated in DR 3 −/− PVAT . Despite this influx, PVAT intact DR 3 −/− constriction responses were restored to the same level as DR 3 WT . Impaired vascular constriction in inflammatory arthritis occurs independently of total MMP ‐9 levels, but correlates with macrophage and neutrophil ingress. Ablating DR 3 worsens the associated vasculature dysfunction, however, DR 3 −/− PVAT is able to protect the aorta against aberrant vasoconstriction caused in this model.