Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery.
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.


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.
Zhang
Lisheng
L
Department of Medicine (Cardiology), Duke University Medical Center, Durham, NC, USA.
Sivashanmugam
Perumal
P
Wu
Jiao-Hui
JH
Brian
Leigh
L
Exum
Sabrina T
ST
Freedman
Neil J
NJ
Peppel
Karsten
K
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology*; D006965:Hyperplasia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D017539:Tunica Intima / Q000503:physiopathology*; D014682:Vena Cava, Inferior / Q000637:transplantation*
D001057:Apolipoproteins E; D017475:Receptors, Nerve Growth Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; C517634:Ngfr protein, mouse