REGULATION OF CEREBRAL BLOOD FLOW IN THE FETUS

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The forces exerted on the human fetal head as it dilates the cervix during normal labor can periodically increase three times that of amniotic fluid pressure and potentially result in transient cerebral ischemia. However, the pathophysiological consequences of fetal head compression has not been well studied in an experimental animal model. In near term fetal sheep (130 days), we found that steady state elevation of intracranial pressure (ICP) resulted in a powerful pressor response that maintained fetal cerebral blood flow and metabolism, but that the response was not sufficiently rapid to defend against cyclic oscillations in ICP. Preliminary data indicate that the pressor response is less effective at mid-gestation (90 days), corresponding to the period of cortical neuronal circuit formation prior to peak myelination. In the present proposal, we will first determine how well cerebrovascular autoregulation maintains cerebral blood flow with moderate elevation of ICP and how effective the pressor response is in maintaining cerebral metabolism with severe elevation of ICP at mid-gestation. We will contrast these defense strategies to those available to the near term fetal sheep. Neuronally generated nitric oxide may be important in synaptic plasticity during development. Decreased cerebral blood flow with nitric oxide synthase inhibition in postnatal animals suggests that tonic nitric oxide production acts to maintain an elevated level of blood flow. We will determine if development of a nitric oxide dependent mechanism between 90 and 130 days gestation is partly responsible for the tripling of basal blood flow and the amplification of hypoxic and autoregulatory responses. We will characterize the effect of periodic head compression of different amplitudes and durations on cortical and striatal blood flow, metabolism and histopathology in 90 and 130 day fetal sheep in utero. By utilizing antagonists of N-methyl-D-aspartate and quisqualate receptors, and selective immunocytochemical markers of injury in fetal sheep brain, we will evaluate the role of excitotoxic injury known to be prominent in postnatal rats with partial ischemia and hypoxia. Therefore, these studies will provide new insights into developmental mechanisms of cerebrovascular regulation in utero and establish a novel model of perinatal cerebral injury that could occur during labor when homeostatic defense mechanisms fail. The consequences of fetal head compression may have an important bearing on premature and term human newborns predisposed to neurological injury by other prenatal factors, and thereby contribute to cerebral palsy and other neurological disabilities.