title: Targeted deletion of the inhibitory NF-kappaB p50 subunit in bone marrow-derived cells improves collateral growth after arterial occlusion.
abstract: OBJECTIVE
  Adaptive collateral artery growth (arteriogenesis) is an important mechanism to maintain tissue perfusion upon arterial obstruction. Leucocytes and inflammatory mediators play a crucial role in this process. Depletion of the nuclear factor kappa B (NF-κB) p50 subunit modulates inflammatory processes in cardiovascular disease. We hypothesized that NF-κB p50 is a regulator of the inflammatory response after arterial occlusion and subsequent collateral perfusion.
  
  
  RESULTS
  Unilateral femoral artery ligation was performed in NF-κB p50-/- and wild-type (Wt, B6/129PF2) mice. Seven days after arterial occlusion, tissue perfusion restoration was significantly enhanced in NF-κB p50-/- mice compared with Wt mice (42.9 ± 3.9 vs. 32.0 ± 2.6% perfusion recovery, P = 0.04). Transplantation of NF-κB p50-/- bone marrow (bm) into Wt mice and vice versa showed that the effect of p50 subunit depletion can be predominantly attributed to the bone marrow-derived circulating cells (NF-κB p50-/- bm in Wt mice 42.1 ± 1.5%, Wt bm in NF-κB p50-/- mice 35.4±1.5% perfusion recovery). Histological analyses revealed a more elaborate extravasation of monocytes in hindlimb tissue of NF-κB p50-/- mice. Chemotaxis assays confirmed the increased migration ability of NF-κB p50-/- monocytes, which may be due to an observed increased integrin expression. Upon stimulation of blood from NF-κB p50-/- and Wt mice more interleukin-6 was produced, confirming the pro-inflammatory phenotype in absence of the p50 subunit.
  
  
  CONCLUSIONS
  Depletion of the NF-κB p50 subunit enhances collateral artery growth. Its absence in circulating cells improves tissue perfusion restoration after femoral artery ligation by increasing macrophage influx into the growing collateral vessels.
authors.affiliation: Laboratory of Experimental Cardiology, UMC, Utrecht, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: de Groot
authors.forename: René T
authors.initials: RT
authors.lastname: Haverslag
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D002634:Chemotaxis, Leukocyte; D003097:Collateral Circulation; D004195:Disease Models, Animal; D005260:Female; D005263:Femoral Artery / Q000601:surgery; D017353:Gene Deletion; D018836:Inflammation Mediators / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008026:Ligation; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D018919:Neovascularization, Physiologic; D013997:Time Factors
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit