Abstract 3372: NfkB P50 Subunit Depletion Enhances Perfusion Restoration after Femoral Artery Ligation in Mice
Background: Adaptive collateral artery growth (arteriogenesis) is an inflammatory process, involving recruitment of circulating leukocytes and expression of Nuclear Factor kappa B (NFkB) dependent cytokines. As previously shown, the lack of the NFkB p50 subunit promotes inflammation-dependent processes, such as post myocardial infarction remodeling. We therefore hypothesized that the absence of the NFkB p50 subunit enhances the inflammatory response after arterial occlusion resulting in an improved arteriogenic response.
Methods and results: NFkB p50−/− (n=40) and corresponding wild type mice (B6/129PF2, n=40) were subjected to unilateral femoral artery ligation and contralateral sham operation. The expression of the NFkB dependent gene MCP-1 was significantly increased in hind limbs that underwent femoral artery ligation compared to sham operated hind limbs (4.8± 1.14 fold p<0.01). Maximum hind limb perfusion under vasodilatation was assessed using fluorescent microspheres 7 days after surgery. Perfusion restoration was significantly enhanced in the p50 −/−animals compared to wild type mice (42.9 ± 3.9 vs. 32.0 ± 2.6 % of sham hindlimb perfusion respectively, p<0.05). Histological sections of the collateral vessels showed an increased perivascular macrophage accumulation in p50−/− mice. This difference became evident on day 3, indicating a faster and stronger inflammatory response. CD68 mRNA expression analysis confirmed these findings, showing a significant upregulation on day 3, which was more prominent in the p50−/− animals (p50−/−: 5.9 ± 1.8 fold; WT: 1.5 ± 0.6 fold, p<0.05).
Conclusion: The NFkB p50 subunit plays an important inhibitory role in collateral artery growth. Its absence improves perfusion restoration after femoral artery ligation by accelerating the inflammatory responses and increasing macrophage influx into the growing collateral vessels.