{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T14:07:24Z","timestamp":1772633244274,"version":"3.50.1"},"reference-count":63,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T00:00:00Z","timestamp":1566864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["1512341"],"award-info":[{"award-number":["1512341"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Glutamine and glutamate transport was greater in the lightest <jats:italic>versus<\/jats:italic> heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid\u2010pregnancy, but this adaptation was insufficient in late pregnancy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6\/J (wild\u2010type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin\u2010like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest <jats:italic>versus<\/jats:italic> heaviest placenta in a litter, unidirectional maternofetal clearance (<jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub>) of <jats:sup>14<\/jats:sup>C\u2010glutamine and <jats:sup>14<\/jats:sup>C\u2010glutamate (<jats:sup>glutamine<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> and <jats:sup>glutamate<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub>) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, <jats:sup>glutamine<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> and <jats:sup>glutamate<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> were higher (P0 <jats:italic>versus<\/jats:italic> wild\u2010type littermates, WTL) at E15.5. At E18.5, <jats:sup>glutamine<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> remained elevated whereas <jats:sup>glutamate<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> was similar between groups. In summary, we provide evidence that <jats:sup>glutamine<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> and <jats:sup>glutamate<\/jats:sup><jats:italic>K<\/jats:italic><jats:sub>mf<\/jats:sub> adapt according to placental size in WT mice. The placenta of the growth\u2010restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp278226","type":"journal-article","created":{"date-parts":[[2019,8,10]],"date-time":"2019-08-10T21:03:58Z","timestamp":1565471038000},"page":"4975-4990","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction"],"prefix":"10.1113","volume":"597","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3224-7043","authenticated-orcid":false,"given":"Kirsty R.","family":"McIntyre","sequence":"first","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"},{"name":"Manchester Academic Health Science Centre, St. Mary's Hospital Manchester University NHS Foundation Trust  Manchester UK"},{"name":"School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences University of Glasgow  Glasgow UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3828-7126","authenticated-orcid":false,"given":"Christina E.","family":"Hayward","sequence":"additional","affiliation":[{"name":"Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health The University of Manchester  Manchester UK"},{"name":"Manchester Academic Health Science Centre, St. Mary's Hospital Manchester University NHS Foundation Trust  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin 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