Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells

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 (P < 0.05). 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 [H-3]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.