The inhibition of placental mTOR signaling leads to fetal growth restriction with abnormal glucose metabolism in different anatomical regions of placentas

Abstract

Introduction

Fetal growth restriction (FGR) is a common pregnancy complication with significant impact on obstetric and birth outcomes. Increasing evidence shows that the inhibition of placental mechanistic target of rapamycin (mTOR) signaling is closely related to FGR. However, the pathogenesis of FGR is not fully consistent presently, which is subject to the methodological divergence.

Methods

Rapamycin was used to construct the FGR mouse model. Hematoxylin & eosin (HE) and periodic acid-schiff (PAS) staining were used to analyze the morphology of mouse placenta. Western blot was used to analyze the expression levels of glucose transporters and key enzymes associated with glycogen metabolism in human/mouse placental tissues in different anatomic layers. HTR-8 cells were treated with dimethyl sulfoxide (DMSO) or rapamycin (2 mM) for 24 h. Cell viability was detected by CCK8 kit. In addition, glycogen concentration in placental tissue or cell samples was detected by Glycogen Assay Kit.

Results

Firstly, we observed a significant reduction of glucose content in different anatomical regions of human small-for-gestational-age (SGA) placenta, also glucose metabolism was undermined to some extent. Then, we found that FGR placentas showed abnormal morphological changes, the glycogen levels in FGR placentas were significantly reduced by quantitative detection. Meanwhile, the expression levels of glucose transporters, Gys1 and p-Gsk3β in FGR placentas were reduced compared to controls. The HTR-8 cells treated with rapamycin revealed decreasing mTOR activity and glycogen levels. In addition, glucose transporter, GYS1, p-GSK3β expressions were all significantly reduced and t-GSK3β level was significantly elevated.

Discussion

Overall, our data indicate that inhibition of placental mTOR signaling may contribute to the occurrence of FGR by altering glucose metabolism.