REGULATION OF CEREBRAL BLOOD FLOW IN THE FETUS

胎儿脑血流的调节

• 批准号: 5215165
• 负责人: RAYMOND C KOEHLER
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5215165
• 关键词: NMDA receptors; amine oxidoreductase; birth; blood flow measurement; brain injury; brain metabolism; cerebral ischemia /hypoxia; embryo /fetus; female; glutamate receptor; growth /development; immunocytochemistry; mechanical pressure; nitric oxide; sheep; vasomotion

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.

扩张子宫颈时施加在人类胎头上的力 正常分娩期间可定期增加三倍 羊水压力并可能导致短暂性脑损伤 缺血。然而，胎头的病理生理后果 压缩尚未在实验动物模型中得到充分研究。 在近期胎羊（130 天）中，我们发现稳态升高 颅内压 (ICP) 导致强烈的升压反应 维持胎儿脑血流量和新陈代谢，但 响应速度不够快，不足以抵御周期性振荡 在ICP中。 初步数据表明升压反应较小 妊娠中期（90天）有效，对应的时期 髓鞘形成高峰之前皮质神经元回路的形成。 在 目前的建议，我们首先要确定脑血管状况如何 自我调节维持脑血流量适度升高 ICP 以及升压反应在维持大脑功能方面的效果如何 妊娠中期ICP严重升高的代谢。 我们将 将这些防御策略与近期可用的防御策略进行对比 胎羊。 神经元产生的一氧化氮可能很重要 发育过程中的突触可塑性。 脑血流量减少 出生后动物的一氧化氮合酶抑制表明 补品一氧化氮的产生可维持血液水平升高 流动。 我们将确定是否发展出一氧化氮依赖性 妊娠 90 至 130 天之间的机制部分负责 基础血流量增加三倍，缺氧和缺氧症状增强 自我调节反应。 我们将描述周期性的影响 不同幅度和持续时间的头部压迫皮质和 90天和130天纹状体血流量、代谢和组织病理学 子宫内的胎儿羊。 利用 N-甲基-D-天冬氨酸拮抗剂 和使君子受体，以及选择性免疫细胞化学标记物 胎儿羊脑损伤，我们将评估兴奋性毒性的作用 已知在部分缺血的产后大鼠中损伤很明显 缺氧。 因此，这些研究将提供新的见解 子宫内和胎儿脑血管调节的发育机制 建立可能发生的围产期脑损伤的新模型 在分娩期间，当体内平衡防御机制失效时。 后果 胎儿头部受压可能对早产和早产有重要影响 足月人类新生儿容易受到其他产前神经损伤 因素，从而导致脑瘫和其他神经系统疾病 残疾。