Fetal cerebral arteries and prenatal alcohol exposure

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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.