Abstract
Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR.
Highlights
Fetal growth restriction (FGR) is a pregnancy complication characterized by abnormal placental function and low birth weight [1]
System A amino acid transport capacity is low in the maternal-facing syncytiotrophoblast microvillous plasma membrane of human FGR placentas [14,15,16], suggesting that impaired placental System A transport contributes to the deficit in fetal nutrient supply
System A activity is attributed to three sodium-coupled neutral amino acid transporter (SNAT) protein isoforms: SNAT1, SNAT2 and SNAT4, which have all been localized to the human placental microvillous membrane [22,23,24,25]
Summary
Fetal growth restriction (FGR) is a pregnancy complication characterized by abnormal placental function and low birth weight [1]. System A amino acid transport capacity is low in the maternal-facing syncytiotrophoblast microvillous plasma membrane of human FGR placentas [14,15,16], suggesting that impaired placental System A transport contributes to the deficit in fetal nutrient supply. System A transporters mediate sodium-dependent, active accumulation of small neutral amino acids from the maternal blood into the syncytiotrophoblast epithelium (reviewed in [17]). System A activity is attributed to three sodium-coupled neutral amino acid transporter (SNAT) protein isoforms: SNAT1, SNAT2 and SNAT4, which have all been localized to the human placental microvillous membrane [22,23,24,25]. Human FGR has been linked to reduced placental SNAT2 abundance [22,26]
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