Alcohol’s Dual Impact on Cerebral Vasculature: Insights into the Autotaxin-LPA-LPP3 Axis

Background: Alcohol consumption impacts cerebrovascular health in a dose-dependent and molecularly complex manner. Recent research highlights the lysophosphatidic acid (LPA) signaling pathway, involving autotaxin and Lipid Phosphate Phosphatase 3 (LPP3), as a critical mediator of vascular responses to alcohol exposure. Methods: Human Brain Microvascular Endothelial Cells (BMVEC) were exposed to ethanol at various concentrations to assess molecular and functional changes using Western blotting and quantitative PCR. Complementary in vivo studies utilized male C57BL/6J mice subjected to 8-week ethanol regimens (low alcohol consumption [LAC]: 0.7 g/kg/day; high alcohol consumption [HAC]: 2.8 g/kg/day) via oral gavage, followed by ischemic stroke induction. Cerebrovascular density, branching, and ischemia/reperfusion (I/R) injury outcomes were systematically evaluated. Results: Ethanol exposure (50mM) significantly elevated autotaxin activity and LPA levels while reducing LPP3 and KLF2 expression in BMVEC. The autotaxin inhibitor PF8380 mitigated ethanol-induced ICAM-1 upregulation and endothelial permeability alterations. In vivo, LAC promoted vascular density, branching, and reduced I/R-related damage and inflammation, suggesting neuroprotective properties. Conversely, HAC impaired vascular branching and exacerbated I/R injury outcomes. Genetic suppression of endothelial LPP3 demonstrated its pivotal role in maintaining vascular homeostasis and function, further substantiating the significance of the autotaxin-LPA-LPP3 axis. Conclusion: This study highlights alcohol’s dose-dependent effects on cerebrovascular health, mediated through the autotaxin-LPA-LPP3 signaling pathway. Low alcohol consumption may confer vascular and neuroprotective benefits, while excessive consumption induces vascular dysfunction and worsens ischemic injury. These findings emphasize the therapeutic potential of targeting the LPA axis for managing alcohol-induced cerebrovascular pathologies, paving the way for more precise interventions. NIH-P20GM121307; HL141998; AA023610; AA025744; AA02574402S1; AA026708; HL141998S1; AA031465 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.