PoFUT1 promotes uterine angiogenesis and vascular remodeling via enhancing the O-fucosylation on uPA

Dandan Zhang,Shuai Liu,Hao Wang,Caixia Liang,Qiu Yan,Yu Yang,Jianwei Liu

doi:10.1038/s41419-019-2005-3

Abstract

Uterine angiogenesis and vascular remodeling play critical roles in determing the normal menstrual cycle and successful pregnancy. Poor uterine angiogenesis usually results in pregnancy failure. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme responsible for O-fucosylated glycan biosynthesis on glycoproteins. However, the dynamic expression and regulation of poFUT1 on the uterine angiogenesis and vascular remodeling remain unknown. Here, we showed that the enlargement of the vascular lumen in the secretory phase was greater than that in the proliferative phase of the uterine endometrium during menstrual cycle; whereas there was a narrower vessel lumen and fewer blood vessels in the decidua from miscarriage patients than in that from healthy pregnancy women. Additionally, the expression of poFUT1 was increased in the uterine endometrium during the secretory phase compared with that in the proliferation phase, and its expression was decreased in the uterus of miscarriage patients compared with that of the healthy pregnancy women. Using hESCs and a mouse model, we demonstrated that poFUT1 increased the O-fucosylation on uPA, and activated of the RhoA signaling pathway, thus facilitating uterine angiogenesis and vascular remodeling. We also provide evidence that poFUT1 promotes hESCs angiogenesis by the decreased stemness of hESCs. These findings reveal a new insight into the uterine angiogenesis and vascular remodeling. The study suggests that poFUT1 could be seen as a novel potential diagnostic and therapeutic target for miscarriage.

Highlights

Uterine angiogenesis and vascular remodeling are critical events during menstrual cycle and pregnancy[1,2]
Exploring Human endometrial stromal cells (hESCs) and a mouse model, we demonstrated that Protein O-fucosyltransferase 1 (poFUT1) increased Ofucosylation on Urokinase-type plasminogen activator (uPA) following the activation of the RhoA-signaling pathway, facilitating uterine angiogenesis and vascular remodeling
Expression of poFUT1 and features of angiogenesis and vascular remodeling in the uterine endometrium of different functional states poFUT1 was expressed in the uterine endometrium, and the immunofluorescent staining showed the higher levels of poFUT1 in the secretory phase compared with those in the proliferative phase, with the highest expression in the decidual phase of early pregnancy; whereas the levels of poFUT1 were decreased in miscarriage patients (Fig. 1a)

Summary

Introduction

Uterine angiogenesis and vascular remodeling are critical events during menstrual cycle and pregnancy[1,2]. In the secretory phase of the menstrual cycle, the uterus is receptive to the implantation of the blastocyst by increasing vasculature and blood flow as well as uterine secretions[3]. The uterine growth is rapid and accompanied by the profound neovascularization and vascular remodeling in order to increase uterine blood flow, which delivers sufficient oxygen and nutrients to the uterus and to the embryo. One of the most common and important post-translational modification, is involved in many physiological and pathological processes, including reproduction and tumorigenesis[9,10]. Protein fucosylation is a type of glycosylation.

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