OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization

Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. We examined apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-)/OX40L-double-deficient (ApoE(-/-)/OX40L(-/-)) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. We also treated high-fat-fed ApoE(-/-) mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE(-/-)/OX40L(-/-) mice compared with ApoE(-/-) mice. Finally, when high-fat-fed ApoE(-/-) mice were transplanted with bone marrow cells from either wild-type or OX40L(-/-) mice, the extent of aortic atheroma was comparable between the two groups. These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.