Alcohol-Induced Dilation of Fetal Cerebral Arteries Is Region-Specific and Mediated by Cannabinoid Receptor 1 in a Sexually Dimorphic Manner

<b>Introduction:</b> Prenatal alcohol exposure (PAE) is a leading cause of birth defects and developmental impairments, resulting in a spectrum of disorders ranging from mild to severe, which are termed fetal alcohol spectrum disorders (FASD). Globally, there is a high prevalence of FASD, and currently, there is no known available cure. PAE most severely impacts the developing brain, causing long-term structural and functional impairments. Cerebral blood circulation plays a critical role in neuronal and overall brain development. Previous studies have shown that PAE leads to a decrease in fetal brain blood flow velocity via fetal cerebral artery dilation, but the specific targets underlying this effect remain largely unknown. <b>Methods and Results:</b> A previous study indicated that a mixture of cannabinoid blockers ablated alcohol-induced vasodilation, but the exact mechanism(s) involved have not been fully elucidated. Here, we investigated the concentration-dependent effects of alcohol on fetal cerebral arteries (anterior, middle, posterior, and basilar) in baboons (<i>Papio</i> sp.) using toxicologically relevant alcohol concentrations. We observed effects best described by polynomial fittings in both male and female fetuses, with low alcohol concentrations (5-30 mM) causing vasodilation. However, the alcohol concentrations that caused maximal dilation varied among cerebral arteries. Quantitative PCR analysis confirmed the presence of cannabinoid receptor 1 (CB1 receptor) but not cannabinoid receptor 2 (CB2 receptor) transcripts in fetal cerebral arteries. Probing of <i>ex vivo</i> pressurized cerebral arteries with a selective CB1 receptor antagonist (AM251) before alcohol exposure at the maximal vasodilating concentration resulted in decreased alcohol effect in the basilar arteries of female fetuses and in the middle cerebral arteries of male fetuses. In addition, liquid chromatography-mass spectrometry revealed no significant changes in endocannabinoid levels (anandamide and 2-arachydoniylglycerol). Our findings suggest that alcohol may activate CB1 receptors independently of endocannabinoid production to trigger vasodilation. <b>Conclusions:</b> In summary, alcohol induces fetal cerebral artery dilation via the CB1 receptor, with regional and sex-specific differences. Our work provides new insights into the role of the fetal cerebrovascular CB1 receptor in the effect of PAE on cerebral circulation.