Targeted deletion of the inhibitory NF-κB p50 subunit in bone marrow-derived cells improves collateral growth after arterial occlusion

AimsAdaptive 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. Methods and 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. Conclusion: 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.