Inverse Regulation of Confluence-Dependent ADAMTS13 and von Willebrand Factor Expression in Human Endothelial Cells

Abstract

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is a zinc-containing metalloprotease also known as von Willebrand factor (vWF)-cleaving protease. Low ADAMTS13 plasma levels are associated with an increased risk of arterial thrombosis, including myocardial infarction and cerebrovascular disease. The expression and regulation of this metalloprotease in human endothelial cells have not been systematically investigated. In this study, we demonstrate that ADAMTS13 expression is inhibited by proinflammatory cytokines tumor necrosis factor-α and interferon-γ as well as by CD40 ligand, which was hitherto unknown. Factors protecting against atherosclerosis such as exposure to continuous unidirectional shear stress, interleukin-10, or different HMG-CoA reductase inhibitors like, e.g., simvastatin, atorvastatin, or rosuvastatin, did not influence ADAMTS13 expression. Unidirectional periodic orbital shear stress, mimicking oscillatory flow conditions found at atherosclerosis-prone arterial bifurcations, had also no effect. In contrast, a reciprocal correlation between ADAMTS13 and vWF expression in endothelial cells depending on the differentiation state was noted. ADAMTS13 abundance significantly rose on both the mRNA and intracellular protein level and also tethered to the endothelial glycocalyx with the degree of confluency while vWF protein levels were highest in proliferating cells but significantly decreased upon reaching confluence. This finding could explain the anti-inflammatory and antithrombotic phenotype of dormant endothelial cells mediated by contact inhibition.

Keywords

ADAMTS13 - CD40 - endothelial cells - von Willebrand factor

Publikationsverlauf

Eingereicht: 03. Dezember 2020

Angenommen: 28. Juni 2021

Artikel online veröffentlicht:
05. August 2021

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