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

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Abstract
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 3 H]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.