title: Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis.
abstract: 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-alpha (TNF-alpha), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF-alpha or p55 receptor. To test this hypothesis, we developed a novel microsphere-based murine model of hindlimb perfusion measurement.
  
  
  RESULTS
  Unilateral femoral arteries of nude (n=9), TNF-alpha(-/-) (n=9), TNF-alpha 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 approximately 50% of normal within 7 days. TNF-alpha(-/-) mice demonstrated a significant reduction (45.1%) in collateral artery perfusion compared with controls (TNF-alpha(-/-) 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-alpha positively modulates arteriogenesis probably via signaling through its p55 receptor.
authors.affiliation: Department of Cardiology, University of Freiburg, Germany. hoefer@med1.ukl.uni-freiburg.de
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Niels
authors.initials: N
authors.lastname: van Royen
authors.forename: John E
authors.initials: JE
authors.lastname: Rectenwald
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bray
authors.forename: Zaher
authors.initials: Z
authors.lastname: Abouhamze
authors.forename: Lyle L
authors.initials: LL
authors.lastname: Moldawer
authors.forename: Michiel
authors.initials: M
authors.lastname: Voskuil
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Piek
authors.forename: Ivo R
authors.initials: IR
authors.lastname: Buschmann
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001783:Blood Flow Velocity; D005263:Femoral Artery / Q000502:physiology; D005456:Fluorescent Dyes; D006614:Hindlimb; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008819:Mice, Nude; D008863:Microspheres; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D005456:Fluorescent Dyes; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha