Research ArticleInter-Organ Communication in Homeostasis and Disease

Adaptive responses in uteroplacental metabolism and fetoplacental nutrient shuttling and sensing during placental insufficiency

Published Online:https://doi.org/10.1152/ajpendo.00046.2023

Glucose, lactate, and amino acids are major fetal nutrients. During placental insufficiency-induced intrauterine growth restriction (PI-IUGR), uteroplacental weight-specific oxygen consumption rates are maintained, yet fetal glucose and amino acid supply is decreased and fetal lactate concentrations are increased. We hypothesized that uteroplacental metabolism adapts to PI-IUGR by altering nutrient allocation to maintain oxidative metabolism. Here, we measured nutrient flux rates, with a focus on nutrients shuttled between the placenta and fetus (lactate-pyruvate, glutamine-glutamate, and glycine-serine) in a sheep model of PI-IUGR. PI-IUGR fetuses weighed 40% less and had decreased oxygen, glucose, and amino acid concentrations and increased lactate and pyruvate versus control (CON) fetuses. Uteroplacental weight-specific rates of oxygen, glucose, lactate, and pyruvate uptake were similar. In PI-IUGR, fetal glucose uptake was decreased and pyruvate output was increased. In PI-IUGR placental tissue, pyruvate dehydrogenase (PDH) phosphorylation was decreased and PDH activity was increased. Uteroplacental glutamine output to the fetus and expression of genes regulating glutamine-glutamate metabolism were lower in PI-IUGR. Fetal glycine uptake was lower in PI-IUGR, with no differences in uteroplacental glycine or serine flux. These results suggest increased placental utilization of pyruvate from the fetus, without higher maternal glucose utilization, and lower fetoplacental amino acid shuttling during PI-IUGR. Mechanistically, AMP-activated protein kinase (AMPK) activation was higher and associated with thiobarbituric acid-reactive substances (TBARS) content, a marker of oxidative stress, and PDH activity in the PI-IUGR placenta, supporting a potential link between oxidative stress, AMPK, and pyruvate utilization. These differences in fetoplacental nutrient sensing and shuttling may represent adaptive strategies enabling the placenta to maintain oxidative metabolism.

NEW & NOTEWORTHY These results suggest increased placental utilization of pyruvate from the fetus, without higher maternal glucose uptake, and lower amino acid shuttling in the placental insufficiency-induced intrauterine growth restriction (PI-IUGR) placenta. AMPK activation was associated with oxidative stress and PDH activity, supporting a putative link between oxidative stress, AMPK, and pyruvate utilization. These differences in fetoplacental nutrient sensing and shuttling may represent adaptive strategies enabling the placenta to maintain oxidative metabolism at the expense of fetal growth.

REFERENCES

  • 1. Hay WW Jr. Energy and substrate requirements of the placenta and fetus. Proc Nutr Soc 50: 321–336, 1991. doi:10.1079/pns19910042.
    Crossref | PubMed | ISI | Google Scholar
  • 2. Murray AJ. Oxygen delivery and fetal-placental growth: beyond a question of supply and demand? Placenta 33, Suppl 2: e16–e22, 2012. doi:10.1016/j.placenta.2012.06.006.
    Crossref | PubMed | ISI | Google Scholar
  • 3. Brown LD, Palmer C, Teynor L, Boehmer BH, Stremming J, Chang EI, White A, Jones AK, Cilvik SN, Wesolowski SR, Rozance PJ. Fetal sex does not impact placental blood flow or placental amino acid transfer in late gestation pregnant sheep with or without placental insufficiency. Reprod Sci 29: 1776–1789, 2022. doi:10.1007/s43032-021-00750-9.
    Crossref | PubMed | ISI | Google Scholar
  • 4. Cetin I, Taricco E, Mandò C, Radaelli T, Boito S, Nuzzo AM, Giussani DA. Fetal oxygen and glucose consumption in human pregnancy complicated by fetal growth restriction. Hypertension 75: 748–754, 2020. doi:10.1161/HYPERTENSIONAHA.119.13727.
    Crossref | PubMed | ISI | Google Scholar
  • 5. Thorn SR, Brown LD, Rozance PJ, Hay WW Jr, Friedman JE. Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin. Diabetes 62: 65–73, 2013. doi:10.2337/db11-1727.
    Crossref | PubMed | ISI | Google Scholar
  • 6. Jones AK, Rozance PJ, Brown LD, Lorca RA, Julian CG, Moore LG, Limesand SW, Wesolowski SR. Uteroplacental nutrient flux and evidence for metabolic reprogramming during sustained hypoxemia. Physiol Rep 9: e15033, 2021. doi:10.14814/phy2.15033.
    Crossref | PubMed | ISI | Google Scholar
  • 7. Char VC, Creasy RK. Lactate and pyruvate as fetal metabolic substrates. Pediatr Res 10: 231–234, 1976. doi:10.1203/00006450-197604000-00006.
    Crossref | PubMed | ISI | Google Scholar
  • 8. Burd LI, Jones MD Jr, Simmons MA, Makowski EL, Meschia G, Battaglia FC. Placental production and foetal utilisation of lactate and pyruvate. Nature 254: 710–711, 1975. doi:10.1038/254710a0.
    Crossref | PubMed | ISI | Google Scholar
  • 9. Gu W, Jones CT, Harding JE. Metabolism of glucose by fetus and placenta of sheep. The effects of normal fluctuations in uterine blood flow. J Dev Physiol 9: 369–389, 1987.
    PubMed | Google Scholar
  • 10. Otey E, Stenger V, Eitzman D, Andersen T, Gessner I, Prystowsky H. Movements of lactate and pyruvate in the pregnant uterus of the human. Am J Obstet Gynecol 90: 747–752, 1964. doi:10.1016/0002-9378(64)90937-8.
    Crossref | PubMed | ISI | Google Scholar
  • 11. Mann LI. Effects in sheep of hypoxia on levels of lactate, pyruvate, and glucose in blood of mothers and fetus. Pediatr Res 4: 46–54, 1970. doi:10.1203/00006450-197001000-00005.
    Crossref | PubMed | ISI | Google Scholar
  • 12. Boyle DW, Meschia G, Wilkening RB. Metabolic adaptation of fetal hindlimb to severe, nonlethal hypoxia. Am J Physiol Regul Integr Comp Physiol 263: R1130–R1135, 1992. doi:10.1152/ajpregu.1992.263.5.R1130.
    Link | ISI | Google Scholar
  • 13. Battaglia FC. Glutamine and glutamate exchange between the fetal liver and the placenta. J Nutr 130: 974S–977S, 2000. doi:10.1093/jn/130.4.974S.
    Crossref | PubMed | ISI | Google Scholar
  • 14. Moores RR Jr, Vaughn PR, Battaglia FC, Fennessey PV, Wilkening RB, Meschia G. Glutamate metabolism in fetus and placenta of late-gestation sheep. Am J Physiol Regul Integr Comp Physiol 267: R89–R96, 1994. doi:10.1152/ajpregu.1994.267.1.R89.
    Link | ISI | Google Scholar
  • 15. Vaughn PR, Lobo C, Battaglia FC, Fennessey PV, Wilkening RB, Meschia G. Glutamine-glutamate exchange between placenta and fetal liver. Am J Physiol Endocrinol Metab 268: E705–E711, 1995. doi:10.1152/ajpendo.1995.268.4.E705.
    Link | ISI | Google Scholar
  • 16. Cetin I, Fennessey PV, Sparks JW, Meschia G, Battaglia FC. Fetal serine fluxes across fetal liver, hindlimb, and placenta in late gestation. Am J Physiol Endocrinol Metab 263: E786–E793, 1992. doi:10.1152/ajpendo.1992.263.4.E786.
    Link | ISI | Google Scholar
  • 17. Regnault TR, de Vrijer B, Galan HL, Wilkening RB, Battaglia FC, Meschia G. Development and mechanisms of fetal hypoxia in severe fetal growth restriction. Placenta 28: 714–723, 2007. doi:10.1016/j.placenta.2006.06.007.
    Crossref | PubMed | ISI | Google Scholar
  • 18. Oh SY, Roh CR. Autophagy in the placenta. Obstet Gynecol Sci 60: 241–259, 2017. doi:10.5468/ogs.2017.60.3.241.
    Crossref | PubMed | Google Scholar
  • 19. Dong J, Shin N, Chen S, Lei J, Burd I, Wang X. Is there a definite relationship between placental mTOR signaling and fetal growth? Biol Reprod 103: 471–486, 2020. doi:10.1093/biolre/ioaa070.
    Crossref | PubMed | ISI | Google Scholar
  • 20. Manning BD, Toker A. AKT/PKB signaling: navigating the network. Cell 169: 381–405, 2017. doi:10.1016/j.cell.2017.04.001.
    Crossref | PubMed | ISI | Google Scholar
  • 21. Day EA, Ford RJ, Steinberg GR. AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol Metab 28: 545–560, 2017. doi:10.1016/j.tem.2017.05.004.
    Crossref | PubMed | ISI | Google Scholar
  • 22. Garcia D, Shaw RJ. AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66: 789–800, 2017. doi:10.1016/j.molcel.2017.05.032.
    Crossref | PubMed | ISI | Google Scholar
  • 23. Long B, Yin C, Fan Q, Yan G, Wang Z, Li X, Chen C, Yang X, Liu L, Zheng Z, Shi M, Yan X. Global liver proteome analysis using iTRAQ reveals AMPK-mTOR-autophagy signaling is altered by intrauterine growth restriction in newborn piglets. J Proteome Res 15: 1262–1273, 2016. doi:10.1021/acs.jproteome.6b00001.
    Crossref | PubMed | ISI | Google Scholar
  • 24. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19: 121–135, 2018. doi:10.1038/nrm.2017.95.
    Crossref | PubMed | ISI | Google Scholar
  • 25. Cai Z, Li CF, Han F, Liu C, Zhang A, Hsu CC, Peng D, Zhang X, Jin G, Rezaeian AH, Wang G, Zhang W, Pan BS, Wang CY, Wang YH, Wu SY, Yang SC, Hsu FC, D’Agostino RB Jr, Furdui CM, Kucera GL, Parks JS, Chilton FH, Huang CY, Tsai FJ, Pasche B, Watabe K, Lin HK. Phosphorylation of PDHA by AMPK drives TCA cycle to promote cancer metastasis. Mol Cell 80: 263–278.e7, 2020. doi:10.1016/j.molcel.2020.09.018.
    Crossref | PubMed | ISI | Google Scholar
  • 26. Klein DK, Pilegaard H, Treebak JT, Jensen TE, Viollet B, Schjerling P, Wojtaszewski JF. Lack of AMPKalpha2 enhances pyruvate dehydrogenase activity during exercise. Am J Physiol Endocrinol Metab 293: E1242–E1249, 2007. doi:10.1152/ajpendo.00382.2007.
    Link | ISI | Google Scholar
  • 27. Roos S, Powell TL, Jansson T. Placental mTOR links maternal nutrient availability to fetal growth. Biochem Soc Trans 37: 295–298, 2009. doi:10.1042/BST0370295.
    Crossref | PubMed | ISI | Google Scholar
  • 28. Gupta MB, Jansson T. Novel roles of mechanistic target of rapamycin signaling in regulating fetal growth. Biol Reprod 100: 872–884, 2019. doi:10.1093/biolre/ioy249.
    Crossref | PubMed | ISI | Google Scholar
  • 29. Percie Du Sert N, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Hurst V, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Würbel H. Reporting animal research: explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol 18: e3000411, 2020. doi:10.1371/journal.pbio.3000411.
    Crossref | PubMed | ISI | Google Scholar
  • 30. Houin SS, Rozance PJ, Brown LD, Hay WW Jr, Wilkening RB, Thorn SR. Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab 308: E306–E314, 2015. doi:10.1152/ajpendo.00396.2014.
    Link | ISI | Google Scholar
  • 31. Vatnick I, Schoknecht PA, Darrigrand R, Bell AW. Growth and metabolism of the placenta after unilateral fetectomy in twin pregnant ewes. J Dev Physiol 15: 351–356, 1991.
    PubMed | Google Scholar
  • 32. Jones AK, Rozance PJ, Brown LD, Goldstrohm DA, Hay WW Jr, Limesand SW, Wesolowski SR. Sustained hypoxemia in late gestation potentiates hepatic gluconeogenic gene expression but does not activate glucose production in the ovine fetus. Am J Physiol Endocrinol Metab 317: E1–E10, 2019. doi:10.1152/ajpendo.00069.2019.
    Link | ISI | Google Scholar
  • 33. Teng C, Battaglia FC, Meschia G, Narkewicz MR, Wilkening RB. Fetal hepatic and umbilical uptakes of glucogenic substrates during a glucagon-somatostatin infusion. Am J Physiol Endocrinol Metab 282: E542–E550, 2002. doi:10.1152/ajpendo.00248.2001.
    Link | ISI | Google Scholar
  • 34. Rozance PJ, Crispo MM, Barry JS, O’Meara MC, Frost MS, Hansen KC, Hay WW Jr, Brown LD. Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation. Am J Physiol Endocrinol Metab 297: E638–E646, 2009. doi:10.1152/ajpendo.00192.2009.
    Link | ISI | Google Scholar
  • 35. Meschia G, Cotter JR, Makowski EL, Barron DH. Simultaneous measurement of uterine and umbilical blood flows and oxygen uptake. Exp Physiol 52: 1–18, 1967. doi:10.1113/expphysiol.1967.sp001877.
    Crossref | ISI | Google Scholar
  • 36. Molina RD, Meschia G, Battaglia FC, Hay WW Jr. Gestational maturation of placental glucose transfer capacity in sheep. Am J Physiol Regul Integr Comp Physiol 261: R697–R704, 1991. doi:10.1152/ajpregu.1991.261.3.R697.
    Link | ISI | Google Scholar
  • 37. Hay WW Jr, Sparks JW, Quissell BJ, Battaglia FC, Meschia G. Simultaneous measurements of umbilical uptake, fetal utilization rate, and fetal turnover rate of glucose. Am J Physiol Endocrinol Metab 240: E662–E668, 1981. doi:10.1152/ajpendo.1981.240.6.E662.
    Link | ISI | Google Scholar
  • 38. Hay WW Jr, Myers SA, Sparks JW, Wilkening RB, Meschia G, Battaglia FC. Glucose and lactate oxidation rates in the fetal lamb. Proc Soc Exp Biol Med 173: 553–563, 1983. doi:10.3181/00379727-173-41686.
    Crossref | PubMed | ISI | Google Scholar
  • 39. Battaglia FC, Meschia G. Principal substrates of fetal metabolism. Physiol Rev 58: 499–527, 1978. doi:10.1152/physrev.1978.58.2.499.
    Link | ISI | Google Scholar
  • 40. Regnault TR, de Vrijer B, Galan HL, Wilkening RB, Battaglia FC, Meschia G. Umbilical uptakes and transplacental concentration ratios of amino acids in severe fetal growth restriction. Pediatr Res 73: 602–611, 2013. doi:10.1038/pr.2013.30.
    Crossref | PubMed | ISI | Google Scholar
  • 41. Carver TD, Hay WW Jr. Uteroplacental carbon substrate metabolism and O2 consumption after long-term hypoglycemia in pregnant sheep. Am J Physiol Endocrinol Metab 269: E299–E308, 1995. doi:10.1152/ajpendo.1995.269.2.E299.
    Link | ISI | Google Scholar
  • 42. Jones AK, Brown LD, Rozance PJ, Serkova NJ, Hay WW Jr, Friedman JE, Wesolowski SR. Differential effects of intrauterine growth restriction and a hypersinsulinemic-isoglycemic clamp on metabolic pathways and insulin action in the fetal liver. Am J Physiol Regul Integr Comp Physiol 316: R427–R440, 2019. doi:10.1152/ajpregu.00359.2018.
    Link | ISI | Google Scholar
  • 43. Rozance PJ, Jones AK, Bourque SL, D’Alessandro A, Hay WW Jr, Brown LD, Wesolowski SR. Effects of chronic hyperinsulinemia on metabolic pathways and insulin signaling in the fetal liver. Am J Physiol Endocrinol Metab 319: E721–E733, 2020. doi:10.1152/ajpendo.00323.2020.
    Link | ISI | Google Scholar
  • 44. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55: 611–622, 2009. doi:10.1373/clinchem.2008.112797.
    Crossref | PubMed | ISI | Google Scholar
  • 45. Cilvik SN, Wesolowski SR, Anthony RV, Brown LD, Rozance PJ. Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth. J Physiol 599: 3403–3427, 2021. doi:10.1113/JP281288.
    Crossref | PubMed | ISI | Google Scholar
  • 46. Chang EI, Wesolowski SR, Gilje EA, Baker PR 2nd, Reisz JA, D’Alessandro A, Hay WW Jr, Rozance PJ, Brown LD. Skeletal muscle amino acid uptake is lower and alanine production is greater in late gestation intrauterine growth-restricted fetal sheep hindlimb. Am J Physiol Regul Integr Comp Physiol 317: R615–R629, 2019. doi:10.1152/ajpregu.00115.2019.
    Link | ISI | Google Scholar
  • 47. Stremming J, Chang EI, Knaub LA, Armstrong ML, Baker PR 2nd, Wesolowski SR, Reisdorph N, Reusch JE, Brown LD. Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth-restricted fetal sheep. Am J Physiol Regul Integr Comp Physiol 322: R228–R240, 2022. doi:10.1152/ajpregu.00222.2021.
    Link | ISI | Google Scholar
  • 48. Brown LD, Rozance PJ, Bruce JL, Friedman JE, Hay WW Jr, Wesolowski SR. Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 309: R920–R928, 2015. doi:10.1152/ajpregu.00197.2015.
    Link | ISI | Google Scholar
  • 49. Chung M, Teng C, Timmerman M, Meschia G, Battaglia FC. Production and utilization of amino acids by ovine placenta in vivo. Am J Physiol Endocrinol Metab 274: E13–E22, 1998. doi:10.1152/ajpendo.1998.274.1.E13.
    Link | ISI | Google Scholar
  • 50. Regnault TR, de Vrijer B, Galan HL, Davidsen ML, Trembler KA, Battaglia FC, Wilkening RB, Anthony RV. The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction. J Physiol 550: 641–656, 2003. doi:10.1113/jphysiol.2003.039511.
    Crossref | PubMed | ISI | Google Scholar
  • 51. Thureen PJ, Trembler KA, Meschia G, Makowski EL, Wilkening RB. Placental glucose transport in heat-induced fetal growth retardation. Am J Physiol Regul Integr Comp Physiol 263: R578–R585, 1992. doi:10.1152/ajpregu.1992.263.3.R578.
    Link | ISI | Google Scholar
  • 52. Sparks JW, Hay WW Jr, Bonds D, Meschia G, Battaglia FC. Simultaneous measurements of lactate turnover rate and umbilical lactate uptake in the fetal lamb. J Clin Invest 70: 179–192, 1982. doi:10.1172/JCI110591.
    Crossref | PubMed | ISI | Google Scholar
  • 53. Limesand SW, Rozance PJ, Smith D, Hay WW Jr. Increased insulin sensitivity and maintenance of glucose utilization rates in fetal sheep with placental insufficiency and intrauterine growth restriction. Am J Physiol Endocrinol Metab 293: E1716–E1725, 2007. doi:10.1152/ajpendo.00459.2007.
    Link | ISI | Google Scholar
  • 54. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11–20, 2008. doi:10.1016/j.cmet.2007.10.002.
    Crossref | PubMed | ISI | Google Scholar
  • 55. Illsley NP, Caniggia I, Zamudio S. Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth? Int J Dev Biol 54: 409–419, 2010. doi:10.1387/ijdb.082798ni.
    Crossref | PubMed | ISI | Google Scholar
  • 56. Zamudio S, Torricos T, Fik E, Oyala M, Echalar L, Pullockaran J, Tutino E, Martin B, Belliappa S, Balanza E, Illsley NP. Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth. PLoS One 5: e8551, 2010. doi:10.1371/journal.pone.0008551.
    Crossref | PubMed | ISI | Google Scholar
  • 57. Brown LD, Rozance PJ, Thorn SR, Friedman JE, Hay WW Jr. Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep. Am J Physiol Endocrinol Metab 303: E352–E364, 2012. doi:10.1152/ajpendo.00059.2012.
    Link | ISI | Google Scholar
  • 58. Jozwik M, Pietrzycki B, Jozwik M, Anthony RV. Expression of enzymes regulating placental ammonia homeostasis in human fetal growth restricted pregnancies. Placenta 30: 607–612, 2009. doi:10.1016/j.placenta.2009.05.005.
    Crossref | PubMed | ISI | Google Scholar
  • 59. Cetin I. Amino acid interconversions in the fetal-placental unit: the animal model and human studies in vivo. Pediatr Res 49: 148–154, 2001. doi:10.1203/00006450-200102000-00004.
    Crossref | PubMed | ISI | Google Scholar
  • 60. Kalhan SC. One carbon metabolism in pregnancy: impact on maternal, fetal and neonatal health. Mol Cell Endocrinol 435: 48–60, 2016. doi:10.1016/j.mce.2016.06.006.
    Crossref | PubMed | ISI | Google Scholar
  • 61. Arroyo JA, Anthony RV, Parker TA, Galan HL. eNOS, NO, and the activation of ERK and AKT signaling at mid-gestation and near-term in an ovine model of intrauterine growth restriction. Syst Biol Reprod Med 56: 62–73, 2010. doi:10.3109/19396360903469307.
    Crossref | PubMed | ISI | Google Scholar
  • 62. Lorca RA, Houck JA, Laurent LC, Matarazzo CJ, Baker K, Horii M, Nelson KK, Bales ES, Euser AG, Parast MM, Moore LG, Julian CG. High altitude regulates the expression of AMPK pathways in human placenta. Placenta 104: 267–276, 2021. doi:10.1016/j.placenta.2021.01.010.
    Crossref | PubMed | ISI | Google Scholar
  • 63. Roos S, Jansson N, Palmberg I, Säljö K, Powell TL, Jansson T. Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth. J Physiol 582: 449–459, 2007. doi:10.1113/jphysiol.2007.129676.
    Crossref | PubMed | ISI | Google Scholar
  • 64. Arroyo JA, Brown LD, Galan HL. Placental mammalian target of rapamycin and related signaling pathways in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol 201: 616.e1–616.e7, 2009. doi:10.1016/j.ajog.2009.07.031.
    Crossref | PubMed | ISI | Google Scholar
  • 65. Tissot van Patot MC, Murray AJ, Beckey V, Cindrova-Davies T, Johns J, Zwerdlinger L, Jauniaux E, Burton GJ, Serkova NJ. Human placental metabolic adaptation to chronic hypoxia, high altitude: hypoxic preconditioning. Am J Physiol Regul Integr Comp Physiol 298: R166–R172, 2010. doi:10.1152/ajpregu.00383.2009.
    Link | ISI | Google Scholar
  • 66. Bell AW, Ehrhardt RA. Regulation of placental nutrient transport and implications for fetal growth. Nutr Res Rev 15: 211–230, 2002. doi:10.1079/NRR200239.
    Crossref | PubMed | ISI | Google Scholar