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.
Copyright © 2020 Elsevier B.V. All rights reserved.
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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- G9521010/MRC_/Medical Research Council/United Kingdom
- MC_PC_14089/MRC_/Medical Research Council/United Kingdom
- MR/M009203/1/MRC_/Medical Research Council/United Kingdom
- PG/15/11/31279/BHF_/British Heart Foundation/United Kingdom
- PG/16/1/31892/BHF_/British Heart Foundation/United Kingdom
- PG/11/40/28891/BHF_/British Heart Foundation/United Kingdom
- PG/15/86/31723/BHF_/British Heart Foundation/United Kingdom
- MC_EX_MR/M009203/1/MRC_/Medical Research Council/United Kingdom
- FS/09/044/28007/BHF_/British Heart Foundation/United Kingdom
- FS/12/82/29736/BHF_/British Heart Foundation/United Kingdom
- PG/13/45/30326/BHF_/British Heart Foundation/United Kingdom