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Thromb Haemost 2015; 114(01): 158-172
DOI: 10.1160/TH14-09-0794
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity

Yunosuke Matsuura
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
2   Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan
,
Atsushi Yamashita
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
,
Takashi Iwakiri
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
2   Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan
,
Chihiro Sugita
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
,
Nozomi Okuyama
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
,
Kazuo Kitamura
2   Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Japan
,
Yujiro Asada
1   Department of Pathology, Faculty of Medicine, University of Miyazaki, Japan
› Author Affiliations
Further Information

Publication History

Received: 24 September 2014

Accepted after major revision: 30 January 2015

Publication Date:
22 November 2017 (online)

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Summary

Atherosclerotic lesions represent a hypoxic milieu. However, the significance of this milieu in atherothrombosis has not been established. We aimed to assess the hypothesis that vascular wall hypoxia promotes arterial thrombus formation. We examined the relation between vascular wall hypoxia and arterial thrombus formation using a rabbit model in which arterial thrombosis was induced by 0.5 %- cholesterol diet and repeated balloon injury of femoral arteries. Vascular wall hypoxia was immunohistochemically detected by pimonidazole hydrochloride, a hypoxia marker. Rabbit neointima and THP-1 macrophages were cultured to analyse prothrombotic factor expression under hypoxic conditions (1 % O2). Prothrombotic factor expression and nuclear localisation of hypoxia-inducible factor (HIF)-1α and nuclear factor-kappa B (NF-κB) p65 were immunohisto-chemically assessed using human coronary atherectomy plaques. Hypoxic areas were localised in the macrophage-rich deep portion of rabbit neointima and positively correlated with the number of nuclei immunopositive for HIF-1α and NF-κB p65, and tissue factor (TF) expression. Immunopositive areas for glycoprotein IIb/IIIa and fibrin in thrombi were significantly correlated with hypoxic areas in arteries. TF and plasminogen activator inhibitor-1 (PAI-1) expression was increased in neointimal tissues and/or macrophages cultured under hypoxia, and both were suppressed by inhibitors of either HIF-1 or NF-κB. In human coronary plaques, the number of HIF-1α-immuno-positive nuclei was positively correlated with that of NF-κB-immuno-positive nuclei and TF-immunopositive and PAI-1-immunopositive area, and it was significantly higher in thrombotic plaques. Vascular wall hypoxia augments the thrombogenic potential of atherosclerotic plaque and thrombus formation on plaques via prothrombotic factor upregulation.

Keywords

Atherothrombosis - hypoxia - hypoxia-inducible factor-1 - nuclear factor-κB - tissue factor

 

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