REGULATION OF CEREBRAL BLOOD FLOW IN THE FETUS

胎儿脑血流的调节

• 批准号: 3782849
• 负责人: RAYMOND C KOEHLER
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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/3782849
• 关键词: NMDA receptors; amine oxidoreductase; birth; blood flow measurement; brain injury; brain metabolism; cerebral ischemia /hypoxia; embryo /fetus; 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.

当宫颈扩张时，施加在人胎头上的力 在正常工作期间可以定期增加三倍的 羊水压力，并有可能导致瞬时大脑 缺血。但是，胎儿的病理生理后果 在实验动物模型中尚未对压缩进行很好的研究。 在近期胎儿绵羊（130天）中，我们发现稳态高程 颅内压（ICP）导致强大的压力响应 维持胎儿的脑血流量和代谢，但 响应不足以防御循环振荡 在ICP中。 初步数据表明，压响应较少 在妊娠中期有效（90天），对应于 髓鞘峰之前的皮质神经元回路形成。 在 目前的建议，我们将首先确定脑血管 自动调节保持脑血流，中等高度 ICP及压力响应在维持大脑方面的有效性 妊娠中期ICP的新陈代谢升高。 我们将 将这些防御策略与可用于短期可用的防御策略进行对比 胎儿绵羊。 神经元产生的一氧化氮在 发育过程中的突触可塑性。 脑血流减少 产后动物中一氧化氮合酶抑制作用表明 补品一氧化氮的产生可维持升高的血液 流动。 我们将确定一氧化氮依赖性的发展是否 妊娠90至130天之间的机制是部分原因 基础血流的三元和缺氧的扩增和 自动调节反应。 我们将表征周期性的效果 皮质上不同振幅和持续时间的头部压缩和 90和130天的纹状体血流，代谢和组织病理学 子宫里的胎儿绵羊。 通过利用N-甲基-D-天冬氨酸的拮抗剂 和Quisqualate受体，以及选择性的免疫细胞化学标记 胎儿绵羊大脑的损伤，我们将评估兴奋性毒性的作用 已知在患有部分缺血的产后大鼠中已知的损伤和 缺氧。 因此，这些研究将为您提供新的见解 子宫内脑血管调节的发育机制 建立可能发生的新型围产期大脑损伤模型 在分娩期间，稳态防御机制失败。 后果 胎儿压缩的压缩可能与过早有关，并且 术语人类新生儿因其他产前而易于神经损伤 因素，从而导致脑瘫和其他神经系统 残疾。