Lysophosphatidic Acid Reduces Ischemic Brain Injury by Attenuating Vascular Permeability Through LPA4 Receptor Signaling.

Blood-brain barrier (BBB) disruption significantly exacerbates secondary injury following ischemic stroke. Although lysophosphatidic acid (LPA) is known to regulate vascular stability, its specific role in preserving BBB integrity during cerebral ischemia remains unclear. Here, we investigated the neuroprotective effects of LPA using a mouse model of distal middle cerebral artery occlusion (dMCAO). Eight- to ten-week-old female C57BL/6 mice received 10 mg/kg LPA intraperitoneally immediately after ischemia, and outcomes were assessed at 48 h after dMCAO via infarct volumetry, edema quantification, BBB permeability assays (Evans blue and FITC-dextran), and transcriptomic analyses. We demonstrate that LPA treatment significantly reduced infarct volume by approximately 60% and attenuated cerebral edema at 48 h post-ischemia; This protection was accompanied by preserved BBB integrity and maintained endothelial claudin-5 expression in the ischemic territory. Single-cell analysis identified selective and sustained expression of the LPA4 receptor in ischemic vascular endothelial cells. Crucially, the protective effects of LPA on infarct size and BBB permeability were abolished in LPA4 receptor-knockout mice. These findings indicate that LPA preserves BBB integrity and mitigates ischemic brain injury via an endothelial LPA4 receptor-dependent mechanism, identifying the LPA-LPA4 signaling axis as a promising therapeutic target for reducing secondary brain injury in ischemic stroke.