Lysophosphatidic acid promotes cutaneous wound healing through vascular maturation and fibroblast activation in a murine model

Abstract

BACKGROUND: Impaired cutaneous wound healing is a major clinical burden, particularly among older individuals and patients with diabetes. Lysophosphatidic acid (LPA) is a bioactive phospholipid with known roles in cell proliferation, migration, and vascular formation; however, its mechanistic contribution in wound repair has not been systematically characterized. Therefore, this study aimed to determine whether topical LPA accelerates wound closure in a murine full-thickness excisional wound model and to elucidate the underlying cellular and molecular mechanisms. METHODS: Full-thickness excisional wounds were created on the dorsal skin of mice, and LPA or vehicle was applied once daily. Wound closure was assessed over 13 days using digital planimetry. Bulk RNA sequencing, quantitative reverse transcription polymerase chain reaction, immunofluorescence, flow cytometry, vascular permeability, and tissue hypoxia assays were employed to delineate the underlying mechanisms. Published single-cell RNA sequencing data from mouse skin were re-analyzed to map LPA receptor expression. RESULTS: Topical LPA accelerated the closure of full-thickness excisional skin wounds. Transcriptomic analysis identified upregulation of gene programs associated with vasculature development and extracellular matrix organization. LPA markedly increased endothelial cell numbers and vessel density. Critically, the vessels formed in LPA-treated wounds subsequently displayed elevated pericyte coverage, reduced permeability, and decreased tissue hypoxia, indicating functional vascular maturation. Concurrently, fibroblast-associated matrix genes were upregulated, collagen deposition was accelerated, and lymphangiogenesis was promoted at the wound site. Single-cell analysis implicated LPAR1 in fibroblasts and LPAR4/LPAR6 in endothelial cells as candidate mediators of these effects. CONCLUSIONS: LPA promotes both vascular maturation and fibroblast activation during wound repair, distinguishing it from classical pro-angiogenic factors. These findings establish LPA as a mechanistically distinct therapeutic candidate and suggest a novel approach for targeting vascular maturation in cutaneous wound care.