Brain Circulatory Adaptations of Fetal Alcohol Spectrum Disorders

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Prenatal alcohol exposure (PAE) can give rise to an array of irreversible damages to the developing fetus, known as fetal alcohol spectrum disorders (FASD). Alcohol's actions during pregnancy are complex and produce a myriad of heterogeneous outcomes that can affect nearly every fetal organ system. To date, no approved therapeutic drug exists for FASD, and the prevalence is estimated to be 3-9% in school-age children in the U.S. Despite nearly every brain region exhibiting vulnerability to PAE, a substantial knowledge gap persists regarding how PAE affects vascular function in the developing brain. Circulatory infrastructure develops concomitantly with the brain, and thus, impairment of brain circulatory function may result in altered nutrient, oxygen, metabolite, and hormone delivery to the brain during critical developmental windows. Delivery of these substrates is essential for proper neurodevelopment, and consequently, alcohol-induced disturbances of substrate delivery to the brain could have a profound effect on neurodevelopmental outcomes. In our established FASD rat model, we generated preliminary data utilizing high frequency ultrasonography in utero which showed that chronic binge PAE impairs middle cerebral artery blood flow and velocity time interval, a widely utilized indicator of resistance. The preliminary data further showed PAE resulted in impaired middle cerebral artery (MCA) agonist-induced dose-dependent vasodilation. In Aim 1, we will test if PAE will alter fetal cranially directed blood flow in our FASD model. To accomplish this aim, we will utilize non-invasive, ultra-high frequency ultrasonography to obtain color and pulse wave Doppler measurements of fetal heart rate, cardiac output, blood flow, and indices of vascular resistance in the major artery network that directly supplies blood to the brain (aorta, internal carotid, and MCA). Aim 2 will test if PAE will compromise the response to perfusion pressure in brain vasculature in early development. To accomplish this aim, we will cannulate the MCA, a major resistance artery that directly supplies the brain, and will assess if PAE-alters adaptations to pressure-dependent vascular responses. Aim 3 will test if PAE induces brain artery dysfunction through impairment of endothelial- derived vasodilatory pathways (NO, PGI2, EDHF). To accomplish this aim, combinations of endothelial-derived vasodilator pathways will be blocked pharmacologically and vascular function will be assessed using arteriography followed by assessment of vasodilatory pathways using RNA-seq, immunoblotting, spectrophotometric assays, and enzyme activity assays. Our proposal explores a new frontier of FASD research by developing the first mechanistic framework for binge alcohol-induced brain circulatory adaptations and identifying alcohol targets in an in vivo model. The current proposal's goals align with NIAAA strategic plan for 2017-2021 – Objective 1C, on the need to investigate the circulatory system; "prenatal alcohol has wide-ranging effects on organs, including the circulatory system…"