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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:284.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Tumor Necrosis Factor Receptor-2 Signaling Attenuates Vein Graft Neointima Formation by Promoting Endothelial Recovery

Lisheng Zhang; Perumal Sivashanmugam; Jiao-Hui Wu; Leigh Brian; Sabrina T. Exum; Neil J. Freedman; Karsten Peppel

From the Departments of Medicine (Cardiology) and Cell Biology (L.Z., P.S., J.-H.W., L.B., S.T.E., M.J.F.), Duke University Medical Center, Durham, NC; and the Center for Translational Medicine (K.P.), Jefferson Medical College, Philadelphia, Pa.

Correspondence to Karsten Peppel or Neil J. Freedman, Jefferson Medical College, 1025 Walnut Street, Rm 311, Philadelphia, PA 19107. E-mail karsten.peppel{at}jefferson.edu or neil.freedman@duke.edu

Abstract

Objective— Inflammation appears intricately linked to vein graft arterialization. We have previously shown that tumor necrosis factor (TNF) receptor-1 (TNFR1, p55) signaling augments vein graft neointimal hyperplasia (NH) and remodeling through its effects on vascular smooth muscle cells (SMCs). In this study we examined the role of TNFR2 (p75) signaling in vein graft arterialization.

Methods and Results— Inferior vena cava-to-carotid artery interposition grafting was performed between p75^–/– and congenic (C57B1/6J) wild-type (WT) mice. Six weeks postoperatively, neointimal and medial dimensions were greater in p75^–/– grafts placed into p75^–/– recipients (by 42% or 60%, respectively; P<0.05), when compared with WT veins grafted into WT recipients. Relative to WT vein grafts, p75 deficiency augmented early (2-week-old) graft vascular cell adhesion molecule (VCAM)-1 expression (by 2.4-fold, P<0.05), increased endothelial cell apoptosis (2-fold), and delayed graft re-endothelialization. Both cellular proliferation in early, and collagen I content of mature (6-week-old) vein grafts were increased (by 70% and 50%, respectively) in p75^–/– grafts. P75 deficiency augmented TNF-induced apoptosis of cultured endothelial cells, but did not affect TNF-stimulated SMC proliferation or migration induced by co-cultured macrophages.

Conclusions— TNF signaling via p75 reduces vein graft neointimal hyperplasia through mechanisms involving reduction of adhesion molecule expression and endothelial cell apoptosis.

In murine IVC grafts implanted into congenic recipient mice, TNF receptor-2 deficiency significantly augmented neointimal hyperplasia, medial expansion, and adhesion molecule expression, while delaying endothelial resurfacing of the graft lumen. As opposed to TNF receptor-1 signaling, activation of TNF receptor-2 does not change SMC proliferation and chemotaxis.

Key Words: TNF • inflammation • vascular remodeling • mouse models • endothelial cells