Fetal Adaptation of Chronic Uterine Blood Flow Reduction

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) is a significant cause of perinatal morbidity and mortality. Maternal conditions that result in reduced uteroplacental blood flow (UtBF) are consistently associated with fetal growth restriction. We have examined the long-term effect of sustained fetal hypoxia due to UtBF reduction on fetal growth in the chronically catheterized sheep. Seven days of UtBF reduction through occlusion of the maternal terminal aorta resulted in reduced placental mass, decreased fetal oxygen delivery, fetal hypoxemia, and fetal growth restriction, manifest as a -50% reduction in linear growth rate. The severity of growth restriction in this model is directly related to the degree of fetal hypoxia. The overall hypothesis is that fetal growth restriction due to chronic UtBF reduction is a physiological adaptation to an inadequate supply of oxygen and nutrients to the fetus and placenta. Specifically, we hypothesize that: 1) Placental transport of amino acids is decreased, not only because of diminished delivery to the placenta, but also as a consequence of impaired placental transport. 2) Protein synthesis is inhibited through impaired translation initiation. As a result, fetal protein accretion (and therefore fetal growth rate) markedly decreases. The ability of the fetus to decrease protein synthesis in response to hypoxia is a physiological adaptation similar to that observed in "hypoxia tolerant" animals. Inhibition of protein synthesis reduces energy consumption in the face of diminished energy production, allowing the fetus to survive. We postulate that adaptive down regulation of protein synthesis is a result of decreased translation initiation. The machinery for translation initiation is regulated by the availability of oxygen, glucose, amino acids, and insulin, and will be most apparent in skeletal muscle. We will address these hypotheses by a series of experiments where UtBF reduction is accompanied by a step-wise supplementation of major substrates (oxygen, glucose, amino acids) and insulin. Placental amino acid transport, overall fetal protein turnover and skeletal muscle protein kinetics, as well as the cellular mechanisms of protein synthesis will be measured. These experiments will provide important and unique insight into the mechanisms by which alterations in uterine blood flow lead to fetal growth restriction. Furthermore, the stepwise institution of substrate replacement will elucidate the mechanisms involved in the down regulation of fetal growth in response to specific substrate deficiencies. These data will be crucial in the design of potential interventions in humans to prevent and/or mitigate fetal growth restriction and its lifelong consequences.
Effective start/end date7/1/026/30/07


  • National Institutes of Health: $341,143.00
  • National Institutes of Health: $339,177.00
  • National Institutes of Health: $321,654.00
  • National Institutes of Health: $329,297.00
  • National Institutes of Health: $334,896.00


  • Medicine(all)

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