ArticleCell death discovery2025
Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.
Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The trial behind it
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Who cites it
4 citing papers in PubMed.
- IGF-1Eb Isoform Immunoreactivity May Be Associated with Placental Dysfunction and Vascular Pathology in Fetal Growth Restriction (FGR).Biomolecules · 2026Article
- The mTOR/AMPK signaling axis in placental dysfunction and preeclampsia: mechanisms and therapeutic targeting with metformin.Molecular biology reports · 2026Review
- Targeting the GSK-3β/mTOR axis: a novel pharmacological strategy for preeclampsia prevention and treatment.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Inducible trophoblast-specific knockdown of mechanistic target of rapamycin impairs placental folate transport in mice.The Journal of nutritional biochemistry · 2026Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Fetal growth restriction (FGR) is associated with inhibition of placental mTOR signaling and amino acid transport. mTOR is a positive regulator of amino acid transport mediated by controlling the plasma membrane trafficking of SNAT2, a System A amino acid transporter isoform, and LAT1 an isoform involved in System L amino acid transport. Inhibition of mTOR complex 1 decreases SNAT2 and LAT1 plasma membrane trafficking by activating of Nedd4-2, an E3 ubiquitin ligase, and inhibition of mTOR Complex 2 decreases the protein expression of Cdc42 which limits transporter trafficking to the plasma membrane. We isolated human primary trophoblast (PHT) cells from FGR placentas and demonstrate that they maintain the in vivo FGR phenotype with increased expression of DEPTOR, an endogenous inhibitor of mTOR, reduced mTOR signaling, increased Nedd4-2 expression, lower expression of Cdc42, and decreased SNAT2 and LAT 1 protein expression in the plasma membrane, and decreased System A and L activity. We silenced DEPTOR in FGR PHT cells using siRNA and found normalized mTOR signaling, Nedd4-2 and Cdc42 protein expression, SNAT2 and LAT1 plasma membrane trafficking and System A and L amino acid transport activity. We also show that hypoxia induces DEPTOR upregulation in PHT cells. In the Healthy Start Study, a longitudinal pre-birth cohort, placental DEPTOR expression was correlated with lower birth weight percentile and with higher systolic and diastolic blood pressure in children at 4-6 years of age. Together, our studies provide mechanistic and translational insight into how placental DEPTOR may serve as potential mediator of fetal growth and long-term health risk. We identify a mechanistic link between increased trophoblast DEPTOR expression in FGR and decreased placental mTOR signaling and amino acid transport. Intervention strategies aimed at normalizing trophoblast mTOR signaling may be effective to improve trophoblast nutrient transport and fetal growth in FGR.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.