Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling

Abstract

Colonization of germ-free mice with microbiota promotes vascular growth in the small intestine through a mechanism involving tissue factor, PAR1 and Ang1. Colonization of germ-free mice with microbiota has been previously reported to promote vascular growth in the small intestine. Understanding the underlying mechanism for this process may provide new therapeutic targets for wound healing and ischaemic conditions, and for modifying the absorptive capacity of the gut. Frederik Bäckhed and colleagues identify three factors involved in microbiota-induced vascular development: tissue factor, PAR1 and Ang-1. The three signalling components are localized in the enterocytes, epithelial cells that are directly exposed to the gut microbiota. 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 intestine1, but little is known about the mechanisms involved. Tissue factor (TF) is the membrane receptor that initiates the extrinsic coagulation pathway2, and it promotes developmental and tumour angiogenesis3,4. 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 angiogenesis5. 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.