Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, U.S.A.
Department of Maternal and Fetal Medicine, Elizabeth Garrett Anderson Institute for Women's Health, University College London WC1E 6HX, U.K.
Clin Sci (Lond). 2021 Sep 17;135(17):2049-2066. doi: 10.1042/CS20210575.
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.
胎儿生长受限（FGR）是一种妊娠并发症，会降低出生体重，显著增加婴儿死亡率和发病率，并与成年后心血管代谢疾病有关。目前尚无针对 FGR 的特定治疗方法。人类 FGR 婴儿的胎盘 SNAT2 （Slc38a2/SNAT2）的丰度较低，该蛋白为胎儿提供生长所需的氨基酸。我们确定了胎盘 Slc38a2/SNAT2 缺乏在胎儿生长受限中的作用机制，假设胎盘特异性 Slc38a2 敲低会导致小鼠发生 FGR。我们通过用短发夹 RNA（shRNA）转导囊胚，实现了胎盘 Slc38a2 的 59%敲低，而不改变胎儿 Slc38a2 的表达。胎盘特异性 Slc38a2 敲低减少了近足月胎儿和胎盘的体重、胎儿存活率、滋养层质膜（TPM）SNAT2 蛋白丰度，以及氨基酸转运系统 A 示踪剂 14C-甲基氨基异丁酸（MeAIB）的绝对和体重特异性胎盘摄取。我们还在一个明确的足月临床队列中测量了人胎盘 SLC38A2 基因表达，发现与适合胎龄（AGA）对照组胎盘相比，晚期而非早期 FGR 胎盘中 SLC38A2 的表达降低。这些结果表明，低胎盘 Slc38a2/SNAT2 导致 FGR，可能成为晚期 FGR 临床治疗的靶点。
