The present study is designed to evaluate the mechanism(s) responsible for fetal growth retardation in response to reduced uteroplacental blood flow. During the last four years we have been developing a model of intrauterine growth retardation (IUGR) using a pregnant sheep model in which uteroplacental blood flow has been mechanically reduced. Studies to data have shown a direct relationship (p less than or equal to 0.01) between uteroplacental blood flow and ponderal index, feta body weight, fetal heart and thymus weights and placental weight. The present study is designed to evaluate the mechanisms responsible for fetal growth retardation in response to reductions in uteroplacental blood flow. The first series of studies is designed to complete validation of the sheep model which has shown that graded reductions in uteroplacental blood flow result in graded decreases in fetal growth during the last five weeks of gestation. The second series of studies will evaluate the mechanism by which reduction in uteroplacental blood flow leads to decreased placental size. We will extensively investigate the mechanism by which umbilical blood flow is decreased and placental resistance is significantly increased in IUGR. Furthermore we plan to carefully evaluate changes which occur with internal and external Doppler ultrasound wave profiles (S/D ratios, pulsatile indices) in response to IUGR and vasoconstrictive agents. Changes in systolic and diastolic velocity ratios will be determined and compared using both implanted Doppler flow probes on the uterine and umbilical circulation and external spectral analysis Doppler waveform equipment. Studies are also designed to evaluate if autoregulation of blood blow occurs in the uterine and umbilical circulation. Further investigations are planned in regard to substrate and oxygen delivery and consumption in IUGR and control fetuses. These studies will include evaluation of delivery, extraction and consumption by the uterus, placenta, and fetus. Finally, the effect of increased uteroplacental perfusion (produced by release of the vascular occluder) on substrate delivery, fetal growth, umbilical vascular resistance and umbilical blood flow will be determined in IUGR animals after the vascular occluders have been returned to pre-occlusion values or after administration of oxygen to mother. These studies will result in significant insight into the mechanism of IUGR.
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