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).


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 [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.
Duke University Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC 27710, USA.
Lisheng
L
Zhang
Karsten
K
Peppel
Leigh
L
Brian
Lynn
L
Chien
Neil J
NJ
Freedman
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017536:Carotid Artery, Common / Q000601:surgery; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D017539:Tunica Intima / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D014680:Veins / Q000201:enzymology / Q000378:metabolism / Q000637:transplantation; D014682:Vena Cava, Inferior / Q000166:cytology / Q000637:transplantation*
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018925:Chemokines; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha