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, 296, 11-17

Effect of a Coronary-Heart-Disease-Associated Variant of ADAMTS7 on Endothelial Cell Angiogenesis

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Effect of a Coronary-Heart-Disease-Associated Variant of ADAMTS7 on Endothelial Cell Angiogenesis

Xiangyuan Pu et al. Atherosclerosis.

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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