Abstract
Mechanistic Target of Rapamycin Complex 2 (mTORC2) regulates placental amino acid and folate transport. However, the role of mTORC2 in modulating other placental functions is largely unexplored. We used a gene array following the silencing of rictor to identify genes regulated by mTORC2 in primary human trophoblast (PHT) cells. Four hundred and nine genes were differentially expressed; 102 genes were down-regulated and 307 up-regulated. Pathway analyses demonstrated that inhibition of mTORC2 resulted in increased expression of genes encoding for pro-inflammatory IL-6, VEGF-A, leptin, and inflammatory signaling (SAPK/JNK). Furthermore, down-regulated genes were functionally enriched in genes involved in angiogenesis (Osteopontin) and multivitamin transport (SLC5A6). In addition, the protein expression of leptin, VEGFA, IL-6 was increased and negatively correlated to mTORC2 signaling in human placentas collected from pregnancies complicated by intrauterine growth restriction (IUGR). In contrast, the protein expression of Osteopontin and SLC5A6 was decreased and positively correlated to mTORC2 signaling in human IUGR placentas. In conclusion, mTORC2 signaling regulates trophoblast expression of genes involved in inflammation, micronutrient transport, and angiogenesis, representing novel links between mTOR signaling and multiple placental functions necessary for fetal growth and development.
Highlights
The intrauterine environment impacts the lifelong health of the fetus (Barker et al, 1993; Gluckman and Hanson, 2004a,b; Gluckman et al, 2008)
To explore the clinical relevance of our findings, we examined the relationship between placental Mechanistic Target of Rapamycin Complex 2 (mTORC2) signaling and protein expression of leptin, VEGF-A, IL-6, Osteopontin, and sodiumdependent multivitamin transporter (SLC5A6) in placentas collected from appropriate-for-gestational age (AGA) and intrauterine growth restriction (IUGR) pregnancies
To further demonstrate the clinical relevance of these findings, we show that mTORC2 signaling activity was negatively correlated to protein expression of leptin, VEGF-A, and IL-6 in placentas from pregnancies complicated by IUGR
Summary
The intrauterine environment impacts the lifelong health of the fetus (Barker et al, 1993; Gluckman and Hanson, 2004a,b; Gluckman et al, 2008). The placenta plays a critical role in regulating the intrauterine environment and orchestrating fetal growth and organ-specific development (Burton and Jauniaux, 2015; Burton et al, 2016). Changes in the maternal compartment or in the intrauterine environment caused by various intrinsic and extrinsic stressors modulate placental function, including nutrient transport, blood flow, metabolism, and hormone secretion. These changes in placental function may adversely impact the developing fetus with potential health consequences across the lifespan (Sandovici et al, 2012). The molecular mechanisms regulating the function of the human placenta are poorly understood (Guttmacher et al, 2014)
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