Direct evidence for tumor necrosis factor-α signaling in arteriogenesis

Imo E. Hoefer, Niels Van Royen, John E. Rectenwald, Elizabeth J. Bray, Zaher Abouhamze, Lyle L. Moldawer, Michiel Voskuil, Jan J. Piek, Ivo R. Buschmann, C. Keith Ozaki

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


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-α (TNF-α), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF-α 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-α-/- (n=9), TNF-α 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-α-/- mice demonstrated a significant reduction (45.1%) in collateral artery perfusion compared with controls (TNF-α-/- 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-α positively modulates arteriogenesis probably via signaling through its p55 receptor.

Original languageEnglish (US)
Pages (from-to)1639-1641
Number of pages3
Issue number14
StatePublished - Apr 9 2002


  • Blood flow
  • Collateral circulation
  • Inflammation
  • Microspheres
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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