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

Xiangyuan Pu, Kenneth Chan, Wei Yang, Qingzhong Xiao, Li Zhang, Andrew D Moore, Chuanju Liu, Tom R Webb, Mark J Caulfield, Nilesh J Samani, Jianhua Zhu, Shu Ye

Atherosclerosis 2020 Mar

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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. 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. 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. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Xiangyuan Pu, Kenneth Chan, Wei Yang, Qingzhong Xiao, Li Zhang, Andrew D Moore, Chuanju Liu, Tom R Webb, Mark J Caulfield, Nilesh J Samani, Jianhua Zhu, Shu Ye. Effect of a coronary-heart-disease-associated variant of ADAMTS7 on endothelial cell angiogenesis. Atherosclerosis. 2020 Mar;296:11-17