Vein Graft Neointimal Hyperplasia Is Exacerbated by Tumor Necrosis Factor Receptor-1 Signaling in

Objective—Vein graft remodeling and neointimal hyperplasia involve inflammation, graft-intrinsic cells, and recruitment of vascular progenitor cells. We sought to examine if the inflammatory cytokine tumor necrosis factor (TNF) affects vein graft remodeling via its p55 TNF receptor-1 (p55). Methods and Results—Inferior vena cava-to-carotid artery interposition grafting was performed between p55/ and congenic (C57Bl/6) wild-type (WT) mice. Immunofluorescence revealed TNF in early (2-week) vein grafts. Six weeks postoperatively, luminal and medial areas were indistinguishable among all vein graft groups. However, neointimal area was reduced in p55/ grafts: by 40 % in p55/ grafts placed in p55/ recipients, and by 21 % in p55/ grafts placed in WT recipients, compared with WT grafts in WT recipients (P0.05). In 2-week-old vein grafts, p55 deficiency reduced intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 expression by 50 % to 60%, and increased the extent of graft endothelialization. In vitro, TNF promoted chemokine expression and [3H]thymidine incorporation in vascular smooth muscle cells (SMCs) from WT, but not from p55/ mice. However, responses of WT and p55/ SMCs to other growth factors were equivalent. Conclusions—Signaling via p55, in vein graft-intrinsic cells, contributes to the pathogenesis of vein graft neointimal hyperplasia. (Arterioscler Thromb Vasc Biol. 2004;24:2277-2283.) Key Words: vascular remodeling inflammation mouse models smooth muscle cells tumor necrosis facto