Abstract: Objective　To explore whether CD137-CD137L signaling pathway can promote angiogenesis in atherosclerosis plaque via activating TNF receptor associated factor 6 (TRAF6). Methods　Endothelial cells (bEnd.3) and the aortic rings from male mice were divided into the following groups: control group (with 10 μg/L TNF-α in culture medium), IgG isotype control group (with 10 μg/L TNF-α+5 mg/L IgG2b in culture medium) and CD137 activated group (with 10 μg/L TNF-α+5 mg/L CD137 antibody in culture medium). Small interfering RNA (siRNA) oligonucleotide was used for TRAF6 gene knockdown in MBVEC and the aortic rings, which were divided into two groups: control siRNA group (control siRNA transfected) and TRAF6 siRNA group (TRAF6 siRNA transfected). Western blot assay was used to determine protein expressions of TRAF6, Smad1/5 and VEGF. Transwell assay was used to observe the migration ability of endothelial cells. Matrigel tube formation was used to test the tube formation ability of endothelial cells and the mouse aortic rings. Angiogenesis assay were used for detecting the aortic ring microangiogenesis. Results　The expression levels of mRNA and protein of TRAF6 and VEGF were significantly higher in CD137 activated group than those in IgG isotype control group and  control group (both in the endothelial cells and aortic rings, P＜0.05). The expression levels of mRNA and protein of TRAF6 and Smad1/5 were significantly lower in TRAF6 siRNA group than those in control siRNA group in endothelial cells and aortic rings. Migration cell number was remarkably lower in TRAF6 siRNA group than that in control siRNA group. Values of the formation of the tube lengthand branch number were both significantly lower in TRAF6 siRNA group than those in control siRNA group. The numbers of microvessels outgrowth were dramatically reduced in aortic rings in control siRNA group (P＜0.05). Conclusion　CD137-CD137L signaling pathway can promote angiogenesis in atherosclerosis plaque by activating TRAF6.

Key words: antigens, CD137, atherosclerosis, TNF receptor-associated factor 6, Smad1 protein, Smad5 protein, angiogenesis