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Atherosclerosis. 2020 Jan 21;296:11-17. doi: 10.1016/j.atherosclerosis.2020.01.015. [Epub ahead of print]

Effect of a coronary-heart-disease-associated variant of ADAMTS7 on endothelial cell angiogenesis.

Author information

1
First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; William Harvey Research Institute, Queen Mary University of London, London, UK.
2
William Harvey Research Institute, Queen Mary University of London, London, UK; Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
3
Shantou University Medical College, Shantou, China.
4
William Harvey Research Institute, Queen Mary University of London, London, UK.
5
First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
6
Musculoskeletal Research Center, New York University School of Medicine, New York, NY, USA.
7
Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.
8
Shantou University Medical College, Shantou, China; Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK. Electronic address: s_ye@stu.edu.cn.

Abstract

BACKGROUND AND AIMS:

Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis.

METHODS AND RESULTS:

ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody.

CONCLUSIONS:

The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.

KEYWORDS:

ADAMTS7; Angiogenesis; Atherosclerosis; Endothelial cell

Conflict of interest statement

Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

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