武汉云克隆科技股份有限公司

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 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.

摘要：肠道微生物群是一个与宿主的生理机能共同进化的复杂的生态系统。微生物群在无菌（GF）小鼠小肠的定植促进了小肠血管密度增加，但我们并不了解其中的机制。组织因子(TF)是启动外源性凝血途径的膜受体，它促进发育和肿瘤血管的形成。我们发现小肠中的微生物促进TF的糖基化与TF在细胞表面的定位、凝血蛋白酶的活性以及TF细胞浆的磷酸化有关。抗TF治疗可抑制小鼠小肠内微生物诱导的血管重塑和促血管生成因子-1(Ang-1)的表达。TF细胞质结构域基因缺失或TF(F3)亚型等位基因缺失的小鼠肠道血管密度降低。TF下游凝血蛋白酶激活蛋白酶受体(PAR)产生血管生成的相关信号。PAR 1缺陷小鼠(F2R−/−)小肠组织中TF胞浆结构域的血管密度和磷酸化均降低，而PAR 2缺陷小鼠(F2RL1−/−)则未见明显下降，凝血酶活性受到抑制表明凝血酶-PAR 1信号是TF磷酸化的上游信号。因此，微生物诱导的血管外TF-PAR 1信号环可能成为影响小肠血管重塑的新途径。

使用试剂原文信息：Measurement of TATcomplexes. The TAT ELISA Kit (Uscnlife, Guangguguoji) was used for determination of the concentration of mouse TAT complexes in lysates of small-intestinal tissue.