Abstract 1669: Effects of Tumor Necrosis Factor Receptors on Inflammation-Mediated Arterial Remodeling
Objective. Tumor necrosis factor (TNF)-alpha is a major pro-inflammatory cytokine and affects cell survival and death through two receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Recent studies suggest that TNF is involved in the pathogenesis of vessel injury and atherosclerosis. However, the effects of the TNF receptors on inflammation-mediated arterial remodeling are not fully understood. Thus, we aimed to investigate the effects of TNFR1 and TNFR2 signals on vessel remodeling in response to inflammation-dependent injury.
Methods. Arterial injury was induced by sheathing a polyethylene cuff around the left femoral artery of TNFR1 knockout (TNFR1KO)(C57BL6/J, n=10), TNFR2 knockout (TNFR2KO)(C57BL6/J, n=10), the wild-type (WT)(C57BL6/J, n=10), TNFR1R2 knockout (TNFR1R2KO)( B6.129SF2/J, n=6) and the WT mice (B6.129SF2/J, n=6). At 4 weeks after vessel injury, the arteries were harvested and the morphology was analyzed by histological evaluation. Immunohistochemical stainings including PCNA staining and TUNEL staining were also performed at 2 weeks and 4 weeks after the injury. Data are expressed as the mean SEM.
Results. TNFR2KO mice (1.4±0.2 μm) and TNFR1R2KO mice (1.9±0.3 μm) showed a significant decrease in neointimal formation compared with WT mice(7.2±1.4 μm; 9.3±1.5 μm, respectively). On the contrary, TNFR1KO mice showed vessel remodeling comparable to WT mice. In addition, in TNFR2KO mice, medial layer thickness was significantly reduced in the injured sites (11.3±0.4 μm), compared with the sham-operated sites (15.4±1.0 μm). At 2 weeks, PCNA-positive nuclei decreased in TNFR2KO (11.2± 1.8%) and TNFR1R2KO mice (12.8±2.8%), compared with WT mice (19.2±3.8%; 22.8±4.2%, respectively). At 2 weeks, TUNEL-positive nuclei were detected in the injured vessel walls of TNFR2KO mice.
Conclusions. TNF plays an important role in neointimal formation and vascular cell proliferation through the two receptors during inflammation-mediated remodeling. TNFR2 is predominantly involved in inducing the effects of TNF on injured vessels, compared with TNFR1.