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Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2

Sven Jäckel, Klytaimnistra Kiouptsi, Maren Lillich, Tim Hendrikx, Avinash Khandagale, Bettina Kollar, Nives Hörmann, Cora Reiss, Saravanan Subramaniam, Eivor Wilms, Katharina Ebner, Marie-Luise von Brühl, Philipp Rausch, John F. Baines, Sandra Haberichter, Bernhard Lämmle, Christoph J. Binder, Kerstin Jurk, Zaverio M. Ruggeri, Steffen Massberg, Ulrich Walter, Wolfram Ruf and Christoph Reinhardt

Key Points

  • VWF synthesis in liver endothelial cells is regulated by gut microbiota through TLR2 signaling.

  • Reduced plasma VWF levels in GF and Tlr2−/− mice cause reduced thrombus formation at the ligation-injured carotid artery.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

The symbiotic gut microbiota play pivotal roles in host physiology and the development of cardiovascular diseases, but the microbiota-triggered pattern recognition signaling mechanisms that impact thrombosis are poorly defined. In this article, we show that germ-free (GF) and Toll-like receptor-2 (Tlr2)-deficient mice have reduced thrombus growth after carotid artery injury relative to conventionally raised controls. GF Tlr2−/− and wild-type (WT) mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between the genotypes. We identify reduced plasma levels of von Willebrand factor (VWF) and reduced VWF synthesis, specifically in hepatic endothelial cells, as a critical factor that is regulated by gut microbiota and determines thrombus growth in Tlr2−/− mice. Static platelet aggregate formation on extracellular matrix was similarly reduced in GF WT, Tlr2−/−, and heterozygous Vwf+/− mice that are all characterized by a modest reduction in plasma VWF levels. Defective platelet matrix interaction can be restored by exposure to WT plasma or to purified VWF depending on the VWF integrin binding site. Moreover, administration of VWF rescues defective thrombus growth in Tlr2−/− mice in vivo. These experiments delineate an unexpected pathway in which microbiota-triggered TLR2 signaling alters the synthesis of proadhesive VWF by the liver endothelium and favors platelet integrin–dependent thrombus growth.

  • Submitted November 29, 2016.
  • Accepted May 22, 2017.
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