Unraveling the Mechanisms of Alcohol-Induced Blood-Brain Barrier Disruption: A Focus on Lysophosphatidic Acid Signaling and Endothelial Cells

About This Grant

Alcohol consumption is a major risk factor for cerebrovascular complications and neuroinflammation, yet the underlying mechanism of alcohol-induced cerebrovascular damage remains unclear. Recent studies suggest that lysophosphatidic acid (LPA) plays a role in blood-brain barrier (BBB) dysfunction through Rho kinase signaling. This proposal presents evidence that heavy alcohol consumption (HAC) enhances cerebrovascular autotaxin levels and decreases lipid phosphate phosphatase-3 (LPP3) expression in brain microvascular endothelial cells, leading to increased LPA signaling in the cerebrovasculature. Reactive oxygen species (ROS) increase in the cerebrovasculature following HAC, promoting autotaxin expression through the redox-sensitive transcription factor NFAT and suppressing LPP3 through miR-92a expression. The proposal aims to investigate the role of autotaxin and LPP3 expression in HAC using cellular, mitochondrial, pharmacological, and molecular biological approaches. The proposed studies will test the hypothesis that the LPA axis critically regulates mitochondrial redox balance, endothelial activation, and neuroinflammation via aggravating BBB damage in HAC. The three specific aims include assessing the effect of alcohol on mitochondrial function and redox balance, evaluating the ability of LPP3 to regulate the alcohol-LPA axis on BBB and neuroinflammation, and assessing the neuroprotective effect of autotaxin blockade to mitigate the impact of HAC in the cerebrovasculature. This proposal presents the first evidence that heavy alcohol consumption (HAC) enhances cerebrovascular LPA signaling, leading to neuroinflammation via aggravating BBB damage, and suggests autotaxin inhibition as a potential therapy for alcohol-induced cerebrovascular damage and LPA signaling. The findings of this study could improve our understanding of the mechanism underlying alcohol-induced cerebrovascular injury and provide a foundation for developing targeted therapies to treat these conditions.