Mammalian target of rapamycin signaling is a mechanistic link between increased endoplasmic reticulum stress and autophagy in the placentas of pregnancies complicated by growth restriction

Introduction: Increased endoplasmic reticulum (ER) stress and autophagy have been noted in the placentas of pregnancies complicated by idiopathic intrauterine growth restriction (IUGR); however, the cause of these phenomena remains unclear. We surmised that oxygen-glucose deprivation (OGD) may increase ER stress and autophagy and that mammalian target of rapamycin (mTOR) signaling is involved in regulating placental ER stress and autophagy in pregnancies complicated by IUGR. Methods: We obtained placentas from women with normal term pregnancies and pregnancies complicated by IUGR to compare ER stress, mTOR signaling, and levels of autophagy-related proteins between the two groups and used primary cytotrophoblast cells treated with or without salubrinal (an ER stress inhibitor), MHY1485 (an mTOR activator), or rapamycin (an mTOR inhibitor) to investigate the effects of OGD on ER stress, mTOR activity, and autophagy levels in vitro. Results: Women with pregnancies complicated by IUGR displayed higher placental ER stress and autophagy levels but lower mTOR activity than women with normal pregnancies. Furthermore, OGD increased ER stress, regulated in development and DNA damage responses-1 (REDD1), phosphorylated tuberous sclerosis complex 2 (TSC2), and autophagy levels and decreased mTOR activity compared to the standard culture condition; however, the salubrinal treatment attenuated these changes. Moreover, the administration of MHY1485 or rapamycin to OGD-treated cells decreased or increased autophagy levels, respectively. Discussion: Based on our results, mTOR is a mechanistic link between OGD-induced ER stress and autophagy in cytotrophoblast cells; thus, mTOR plays an essential role in the pathogenesis of pregnancies complicated by IUGR. (c) 2017 Elsevier Ltd. All rights reserved.