Abstract
Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway.
Highlights
Intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity and mortality [1] and with increased risk of adult diseases such as diabetes, hypertension, and coronary artery disease [2]
This increased fetal growth is likely to be, at least in part, due to increased expression of placental amino acid transporters mediated by mammalian target of rapamycin (mTOR)
These findings suggest a potential approach to intrauterine treatment of fetal growth restriction that may be clinically acceptable
Summary
Intrauterine growth restriction (IUGR) is associated with increased perinatal morbidity and mortality [1] and with increased risk of adult diseases such as diabetes, hypertension, and coronary artery disease [2]. Sustained poor growth in utero frequently results in the fetus being delivered [4], with the attendant morbidity and mortality of preterm birth. Preterm birth is itself associated with hypertension [5], diabetes and insulin resistance [6], ischemic heart disease and stroke [7] in later life. It is unclear whether intervention early in postnatal life can ameliorate these increased risks. Attempting to reverse IUGR in utero may represent the optimum approach [10]
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