Targeted deletion of the inhibitory NF-kappaB p50 subunit in bone marrow-derived cells improves collateral growth after arterial occlusion.
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.
de Groot
Daphne
D
Laboratory of Experimental Cardiology, UMC, Utrecht, The Netherlands.
Haverslag
René T
RT
Pasterkamp
Gerard
G
de Kleijn
Dominique P V
DP
Hoefer
Imo E
IE
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
D018836:Inflammation Mediators; D015850:Interleukin-6; D052002:NF-kappa B p50 Subunit