title: OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku Sendai 980-8574, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakano
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kagaya
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D014651:Vasa Vasorum / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D001057:Apolipoproteins E; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors