Placenta-specific Slc38a2/SNAT2 knockdown causes fetal growth restriction in mice. Issue 17 (17th September 2021)

• Record Type: Journal Article
• Authors: Vaughan, Owen R.; Maksym, Katarzyna; Silva, Elena; Barentsen, Kenneth; Anthony, Russel V.; Brown, Thomas L.; Hillman, Sara L.; Spencer, Rebecca; David, Anna L.; Rosario, Fredrick J.; Powell, Theresa L.; Jansson, Thomas
• Is Part Of: Clinical science. Volume 135:Issue 17(2021)
• Page Start: 2049
• Page End: 2066
• Publication Date: 2021-09-17
• Subjects: amino acid transport system A -- fetal growth restriction -- lentivirus -- maternal-fetal exchange -- MeAIB -- syncytiotrophoblast; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20210575
• Languages: English
• ISSNs: 0143-5221

Abstract

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, 14 C-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.