Abstract 5159: Arterial Wall Expression of Tumor Necrosis Factor Receptor-2 Attenuates Atherosclerosis by Reducing Recruitment of Monocyte/Macrophages

Abstract

Deficiency of tumor necrosis factor receptor-2 (TNFR2) increases TNF-induced endothelial cell apoptosis, decreases the rate of vein graft re-endothelialization, and consequently increases vein graft neointimal hyperplasia. We therefore tested the hypothesis that TNFR2 expression in the arterial wall protects against atherogenesis, by placing common carotid arterial interposition isografts from tnfr2 −/− or congenic wild type (WT) mice into the common carotid arteries of congenic apolipoprotein E −/− mice fed normal chow. We used a procedure we previously demonstrated engenders typical atherosclerosis, but in an accelerated time frame. Grafts were harvested 7 weeks post-op, perfusion-fixed, paraffin-embedded, sectioned at 4 μ m, and stained for collagen and elastin. Computerized morphometry was performed by observers blinded to specimen identity. Eccentric lesions with fibrous caps and necrotic cores developed, and demonstrated up to 85% luminal stenosis. Compared with WT carotid grafts (n=6), tnfr2 KO carotid grafts (n=5) demonstrated significantly more atherosclerosis, with 33% greater neointimal area (0.16±0.03 vs. 0.12±0.01 mm 2 , p<0.01). However, medial area was equivalent in WT and tnfr2 KO arteries (0.12±0.02 vs. 0.10±0.04 mm 2 ). Outward remodeling tended to be greater in tnfr2 KO arteries (external diameter was 14±1% greater); consequently, luminal stenosis was comparable between tnfr2 KO and WT arteries (89±8% vs. 86±14%). Tnfr2 KO arteries not only developed larger neointimal lesions but also showed evidence for more unstable plaque composition: macrophage prevalence was 80±10% higher (p<0.05), and SMC prevalence was 43±5% lower in tnfr2 KO than in WT arteries (p<0.05), as assessed by quantitative immunofluorescence microscopy for F4/80 (macrophages) and SMC α -actin (normalized to Hoechst 33342-stained nuclear fluorescence). Concordantly, immunofluorescence of vascular cell adhesion molecule-1 per cell was 70±20% greater in tnfr2 KO carotid grafts (p<0.05). We conclude that TNFR2 expression in arterial wall cells protects against atherogenesis, by mechanisms that reduce monocyte/macrophage recruitment to the atheroma.