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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2277.)
© 2004 American Heart Association, Inc.

Vascular Biology

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

Lisheng Zhang; Karsten Peppel; Leigh Brian; Lynn Chien; Neil J. Freedman

From Duke University Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC.

Correspondence to Karsten Peppel or Neil J. Freedman, Box 3187, Duke University Medical Center, Durham, NC 27710. E-mail karsten.peppel{at}duke.edu or neil.freedman@duke.edu

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 [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.

In surgical mouse chimeras, TNF receptor-1 (p55)-deficient vein grafts (compared with WT grafts) demonstrated less ICAM-1, VCAM-1, and MCP-1 expression, accelerated endothelialization, and reduced neointimal hyperplasia. However, vein graft medial thickness was unaffected. SMC chemokine expression and DNA synthesis in response to TNF, but not PDGF, was abrogated by p55 deficiency.

Key Words: vascular remodeling • inflammation • mouse models • smooth muscle cells • tumor necrosis factor

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