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

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.