Positive TNF rule in arteriogenesis.
(Circulation. 2002;105:1639.)
© 2002 American Heart Association, Inc
Direct Evidence for Tumor Necrosis Factor- Signaling in Arteriogenesis
Imo E. Hoefer, MD; Niels van Royen, MD; John E. Rectenwald, MD; Elizabeth J. Bray, MD; Zaher Abouhamze, BS; Lyle L. Moldawer, PhD; Michiel Voskuil, MD; Jan J. Piek, MD PhD; Ivo R. Buschmann, MD; C. Keith Ozaki, MD
From the Department of Cardiology, University of Freiburg, Germany; Department of Surgery (J.E.R., E.J.B., Z.A., L.L.M., C.K.O.), University of Florida College of Medicine and the Malcolm Randall VAMC, Gainesville, Fla; and Department of Cardiology (M.V., J.J.P.), University of Amsterdam, the Netherlands.
Correspondence to Imo Hoefer, MD, Department of Cardiology, University of Freiburg Hugstetterstr. 55 D-79106, Freiburg, Germany. E-mail hoefer@med1.ukl.uni-freiburg.de
Background— Arteriogenesis serves as an efficient mechanism for flow restoration after arterial occlusion. This process is associated with inflammatory mediators such as tumor necrosis factor- (TNF-), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF- or p55 receptor. To test this hypothesis, we developed a novel microsphere-based murine model of hindlimb perfusion measurement.
Methods and Results— Unilateral femoral arteries of nude (n=9), TNF--/- (n=9), TNF- receptor p55-/- (n=8), and p75-/- (n=8) mice as well as their appropriate genetic background controls were occluded. The nude mice underwent laser Doppler hindlimb flux measurements preoperatively, postoperatively, and after 7 days. Seven days after ligation, all animals underwent tissue perfusion determinations using fluorescent microspheres. Laser Doppler findings confirmed acute decrease in flux with falsely normal values after 1 week. Microsphere results from control mice showed perfusion restoration to values 50% of normal within 7 days. TNF--/- mice demonstrated a significant reduction (45.1%) in collateral artery perfusion compared with controls (TNF--/- 22.4±5.1% versus B6x129 49.7±9.3%; P<0.01). p55-/- mice exhibited an almost identical 45.8% reduction in collateral artery formation (p55-/- 28.3±4.3% versus C57BL/6J 61.8±9.1%; P<0.01), whereas p75-/- mice were equivalent to controls (p75-/- 54.5±5.5%; P=0.13).
Conclusions— Microsphere techniques in mice offer a tool for the molecular dissection of arteriogenesis mechanisms. These results suggest that TNF- positively modulates arteriogenesis probably via signaling through its p55 receptor.
Key Words: collateral circulation • inflammation • microspheres • blood flow • remodeling |
