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Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling

Journal article
Authors Christopher Reinhardt
Mattias Bergentall
Thomas U. Greiner
Florence Schaffner
Gunnel Östergren Lundén
Lars C. Petersen
Wolfram Ruf
Fredrik Bäckhed
Published in Nature
Volume 483
Pages 627-631
ISSN 00280836
Publication year 2012
Published at Wallenberg Laboratory
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 627-631
Language en
Links dx.doi.org/10.1038/nature10893
Subject categories Gastroenterology and Hepatology, Internal medicine

Abstract

The gut microbiota is a complex ecosystem that has coevolved with host physiology. Colonization of germ-free (GF) mice with a microbiota promotes increased vessel density in the small intestine, but little is known about the mechanisms involved. Tissue factor (TF) is the membrane receptor that initiates the extrinsic coagulation pathway, and it promotes developmental and tumour angiogenesis. Here we show that the gut microbiota promotes TF glycosylation associated with localization of TF on the cell surface, the activation of coagulation proteases, and phosphorylation of the TF cytoplasmic domain in the small intestine. Anti-TF treatment of colonized GF mice decreased microbiota-induced vascular remodelling and expression of the proangiogenic factor angiopoietin-1 (Ang-1) in the small intestine. Mice with a genetic deletion of the TF cytoplasmic domain or with hypomorphic TF (F3) alleles had a decreased intestinal vessel density. Coagulation proteases downstream of TF activate protease-activated receptor (PAR) signalling implicated in angiogenesis. Vessel density and phosphorylation of the cytoplasmic domain of TF were decreased in small intestine from PAR1-deficient (F2r-/-) but not PAR2-deficient (F2rl1-/-) mice, and inhibition of thrombin showed that thrombin-PAR1 signalling was upstream of TF phosphorylation. Thus, the microbiota-induced extravascular TF-PAR1 signalling loop is a novel pathway that may be modulated to influence vascular remodelling in the small intestine. © 2012 Macmillan Publishers Limited. All rights reserved.

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