Abstract Children prenatally exposed to alcohol, has potential birth defects and health problems since the central nervous system is sensitive to teratogens as well as from alcohol-related changes in brain structure. The underlying pathophysiology of these events involves lipids within susceptible arteries leading to subsequent localized inflammation and vascular dysfunction. While the bioactive glycerophospholipid lysophosphatidic acid plays a well-known role in atherosclerotic disease, its role in alcohol-mediated prenatal cerebral dysfunction remains virtually unexplored. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that prenatal alcohol exposure enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. Upon prenatal alcohol exposure, reactive oxygen species (ROS) increases in the cerebrovasculature, whereas the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) has been shown to bind to the autotaxin promoter and induce its expression. Furthermore, alcohol transactivates microRNA-92a, which is a negative regulator of LPP3. Thus, we hypothesize that prenatal alcohol exposure alters autotaxin and LPP3 expression to drive lysophosphatidic acid signaling and cerebrovascular dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific Aim 1 will assess the role of prenatal alcohol exposure induced oxidative stress on autotaxin expression and lysophosphatidic acid production in the cerebrovasculature. Specific Aim 2 will determine the role of prenatal alcohol exposure induced oxidative stress on LPP3 depletion and lysophosphatidic acid production in the cerebrovasculature. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect following prenatal alcohol exposure. Our results should provide specific insight into signaling systems mediated by prenatal alcohol exposure and may provide novel targets for treatment and might improve cerebrovascular disorders.