Fetal cerebral arteries and prenatal alcohol exposure

在美国，胎儿酒精谱系障碍(FASD)是导致生长迟缓的主要可预防原因 和儿童的神经发育迟缓。目前，还没有现成的治疗方法 怀孕期间有意或意外接触酒精并导致FASD。这种治疗手段的缺乏 对策在很大程度上归因于缺乏对FASD发病机制的了解。而当 产前酒精暴露(PAE)针对多种组织类型和系统，大脑是最严重的 受影响的器官。有PAE病史的人胎儿和婴儿尸检文件异常 脑血管形成和缺氧缺血神经细胞改变或解决脑出血。工作于 动物模型表明，母体血液酒精水平平均为80-85 mg/dL的PAE可以扩张胎儿 活体脑动脉不受体循环、胎心功能、血脑屏障、 血液pH值，或PO2。胎儿大脑动脉扩张的病理生理学意义预计为 很深刻。首先，一种与酒精无关的病理--自发性低颅压是其特征。 临床上由脑部血流速度下降引起的儿童头骨形态异常所致。 值得注意的是，颅面畸形是人类FASD的中心诊断标准。第二, 酒精引起的胎儿大脑动脉扩张先于暴露的狒狒胎儿的生长延迟。第三, 在绵羊物种中，对PAE反应最大的神经元损失发生在表现出 酒精对脑血管的影响最大。总而言之，临床和实验数据表明， 胎儿大脑动脉内径可能在FASD的病理生理机制中起重要作用。胎儿的范围 脑血管成分在FASD发病机制中的作用仍有待证实。因为我们 最近报道，酒精对体外培养的狒狒胚胎脑动脉的扩张可被一种鸡尾酒完全消融。 内源性大麻素受体1和2(CB1和CB2)的阻断剂。目前的提案将利用 通过靶向胎儿酒精暴露的不同成分来研究胎儿酒精暴露的影响 ECB系统对胎儿脑动脉内径及胎儿生长发育的影响。在子目标1.1中，我们将在体外使用 来自胎儿的加压脑动脉、选择性药物调节剂和质量 内源性产生的大麻素的光谱来检验酒精诱导的血管扩张的假说 胎儿大脑动脉是通过欧洲央行系统的不同组成部分进行调节的。在子目标1.2中，我们将使用 CB受体的药理调节剂、体内无创多普勒超声和液体 色质联用蛋白质组学验证药物阻断细胞外基质的假说 ECB体内系统钝化酒精诱导的胎脑动脉扩张并减轻小鼠生长延迟 胎儿头骨、脑和血管组织。胎儿大脑动脉主宰机制的表征(S) 对酒精的反应将为开发对抗PAE后果的疗法铺平道路。

In the US, fetal alcohol spectrum disorders (FASD) represent the leading preventable cause of growth delay and neurodevelopmental retardation in children. Currently, there are no readily available cures against intended or accidental alcohol exposure during pregnancy and resulting FASD. This lack of therapeutic countermeasures is largely attributed to the lack of a mechanistic understanding of FASD pathogenesis. While prenatal alcohol exposure (PAE) targets multiple tissue types and systems, the brain is the most severely affected organ. Autopsy cases on human fetuses and infants with a history of PAE document abnormal vascularization of the brain and hypoxic-ischemic neuronal changes or resolving brain hemorrhage. Work on animal models demonstrates that PAE with maternal blood alcohol levels averaging 80-85 mg/dL dilates fetal cerebral arteries in vivo independent of changes in systemic circulation, fetal heart function, blood-brain barrier, blood pH, or pO2. The pathophysiological significance of dilated fetal cerebral arteries is expected to be profound. First, an alcohol‐unrelated pathology, spontaneous intracranial hypotension, is characterized clinically by morphological abnormalities of the child’s skull that result from a drop in cerebral blood velocity. Remarkably, craniofacial malformations serve as the central diagnostic criteria for FASD in humans. Second, alcohol-induced dilation of fetal cerebral arteries precedes the growth delay of exposed baboon fetuses. Third, in ovine species, the largest neuronal loss in response to PAE is observed in brain areas that exhibit the highest cerebrovascular alterations by alcohol. Altogether, clinical and experimental data suggest that changes in fetal cerebral artery diameter may play a critical role in the pathophysiology of FASD. The extent of the fetal cerebrovascular component contribution to the pathogenesis of FASD remains to be documented. As we recently reported, alcohol-induced dilation of fetal baboon cerebral arteries in vitro is fully ablated by a cocktail of blockers of the endocannabinoid receptors 1 and 2 (CB1 and CB2). The current proposal will utilize a baboon model to investigate the impact of fetal alcohol exposure by targeting the distinct components of the eCB system on fetal cerebral artery diameter and fetal growth delay. In sub-aim 1.1, we will use in vitro pressurized cerebral arteries from fetal baboons, selective pharmacological modulators, and mass spectrometry of endogenously produced cannabinoids to test the hypothesis that alcohol-induced dilation of fetal cerebral artery is mediated via distinct components of the eCB system. In sub-aim 1.2, we will use pharmacological modulators of CB receptors, non-invasive Doppler ultrasonography in vivo, and liquid chromatography-mass spectrometry proteomics to test the hypothesis that pharmacological blocking of the eCB system in vivo blunts alcohol-induced dilation of fetal cerebral arteries and diminishes the growth delay of fetal skull, brain, and vascular tissue. Characterization of the mechanism(s) that govern fetal cerebral artery responses to alcohol will pave the way for the development of therapeutics against consequences of PAE.