title: Characterization of death receptor 3-dependent aortic changes during inflammatory arthritis.
abstract: 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 (DR3). mCIA was induced in wild-type (WT) and DR3-/-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), DR3, and MMP-9 was determined using immunohistochemistry. In WTs, arthritis-induced vascular dysfunction was associated with increased F4/80+ macrophages and increased DR3 expression in the aorta and PVAT. MMP-9 was also up-regulated in PVAT, but did not correlate with alterations of PVAT intact constriction. DR3-/-mice inherently showed increased leukocyte numbers and MMP-9 expression in the PVAT, but retained the same nonarthritic constriction response as DR3WT mice ±PVAT. Arthritic DR3-/-mice had a worsened constriction response than DR3WT and showed an influx of neutrophils to the aorta and PVAT. Macrophage numbers were also up-regulated in DR3-/-PVAT. Despite this influx, PVAT intact DR3-/-constriction responses were restored to the same level as DR3WT. Impaired vascular constriction in inflammatory arthritis occurs independently of total MMP-9 levels, but correlates with macrophage and neutrophil ingress. Ablating DR3 worsens the associated vasculature dysfunction, however, DR3-/-PVAT is able to protect the aorta against aberrant vasoconstriction caused in this model.
authors.affiliation: Division of Infection and Immunity Cardiff University School of Medicine Cardiff United Kingdom.
authors.forename: Jessica O
authors.initials: JO
authors.lastname: Williams
authors.affiliation: Division of Infection and Immunity Cardiff University School of Medicine Cardiff United Kingdom.
authors.forename: Eddie C Y
authors.initials: EC
authors.lastname: Wang
authors.affiliation: Division of Medical Education Cardiff University School of Medicine Cardiff United Kingdom.
authors.forename: Derek
authors.initials: D
authors.lastname: Lang
authors.affiliation: Division of Infection and Immunity Cardiff University School of Medicine Cardiff United Kingdom.
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
keywords: Death receptor 3; inflammatory arthritis; inflammatory ingress; vascular constriction