A small GTPase, RHOH, is upregulated in the uterus during miscarriage in human and mouse model.

INTRODUCTION

The small GTPase RAC1 is crucial for blastocyst attachment to the endometrium during embryo implantation. RAC1 is regulated by RHOH, whose role in pregnancy establishment we investigated.

METHODS

We analyzed uterine RHOH expression by immunoblotting during the endometrial receptivity window for embryo attachment and miscarriage (LPS-, and IFN-γ-induced), and abortion (RU-486-, and ormeloxifene-induced), using a mouse model, human-origin placenta and decidua-placenta, and human endometrial epithelial cells. Additionally, we determined the cellular localization of RHOH by immunohistochemistry.

RESULTS

RHOH levels were elevated in placentas from human miscarriage cases (n = 7) and in decidua-placenta tissues (n = 13) from these cases. In the mouse model, RHOH expression was downregulated at the implantation site during both receptive and post-receptive stages. Conversely, during pseudopregnancy, uterine RHOH expression was higher in the pre-receptive stage. RHOH was primarily localized in stromal and epithelial cells at all stages examined. In the decidualized uterus, RHOH expression was reduced and predominantly detected in stromal cells. Additionally, upregulation of RHOH was observed in the uterus from miscarriage/abortion cases and inter-implantation sites in non-miscarriage/abortion mouse models. Furthermore, the downstream effector RAC1 was also increased in the miscarriage/abortion mouse models.

DISCUSSION: RHOH was upregulated in the placenta and decidua-placenta tissues of human miscarriage cases. Similarly, in mouse models, RHOH expression increased in the endometrium during miscarriage/abortion. In contrast, RHOH expression decreased at implantation sites and in the decidualized endometrium. These findings suggest that RHOH functions as a regulator of endometrial receptivity, potentially involving RAC1, and that their upregulation is associated with miscarriage/abortion.