Rosario Fredrick J, Barentsen Kenneth, Powell Theresa L, Urschitz Johann, Brown Thomas L, Kanai Yoshikatsu, Jansson Thomas
Department of Obstetrics and Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
PNAS Nexus. 2024 Jun 18;3(6):pgae207. doi: 10.1093/pnasnexus/pgae207. eCollection 2024 Jun.
Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a transgene, we achieved trophoblast-specific overexpression of OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.
胎盘系统L氨基酸转运体活性在合并宫内生长受限（IUGR）的妊娠中降低，而在胎儿过度生长时升高。然而，胎盘大中性氨基酸转运体小亚基1（Slc7a5/LAT1）的表达/活性变化是否在机制上与胎盘功能和胎儿生长相关尚不清楚。我们假设滋养层特异性过表达可增加必需氨基酸的胎盘转运，激活胎盘雷帕霉素机制靶点（mTOR）信号，并促进小鼠胎儿生长。通过用转基因慢病毒转导囊胚，我们实现了滋养层特异性过表达OX，胎儿体重增加了27%，胎盘重量增加了10%。滋养层特异性过表达增加了滋养层质膜（TPM）LAT1蛋白丰度以及TPM系统L转运体活性（增加53%）和系统A转运体活性（增加21%）。过表达还增加了体内亮氨酸的跨胎盘转运（增加85%），但未增加系统A示踪剂14C-甲基氨基异丁酸的跨胎盘转运。通过S6核糖体蛋白（Ser 235/236）磷酸化增加（44%）评估，滋养层特异性过表达OX激活了胎盘mTORC1，通过PKCα-Tyr-657磷酸化（47%）和Akt-Ser 473磷酸化（96%）表明激活了mTORC2。这是首次证明必需氨基酸的胎盘转运在机制上与胎儿生长相关。人类IUGR中胎盘系统L活性降低以及某些胎儿过度生长情况下该转运体的胎盘活性增加可能直接导致这些妊娠并发症的发生。
