Gut microbiota regulate hepatic von Willebrand Factor synthesis and arterial thrombosis via Toll-like receptor-2

The symbiotic gut microbiota plays pivotal roles in host physiology and is associated with the development of cardiovascular diseases, but microbiota-triggered pattern recognition signaling mechanisms impacting thrombosis are poorly defined. Here, we show that germ-free and Toll-like receptor (Tlr) 2-deficient mice have reduced thrombus growth following carotid artery injury relative to conventionally raised controls. Germ-free Tlr2-/- and wild-type mice were indistinguishable, but colonization with microbiota restored a significant difference in thrombus growth between 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 the extracellular matrix protein laminin was similarly reduced in germ-free wild-type, Tlr2-/-, and heterozygous Vwf+/- mice with a modest reduction in plasma VWF level. Defective matrix interaction can be restored by exposure to wild-type plasma or to purified VWF involving 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 pro-adhesive VWF by the liver endothelium and favors platelet integrin-dependent thrombus formation.