Lysophosphatidic acid and sphingosine 1-phosphate stimulate endothelial cell wound healing

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate(S1P) are potent lipid growth factors with similar abilities tostimulate cytoskeleton-based cellular functions. Their effects aremediated by a subfamily of G protein-coupled receptors (GPCRs) encoded by endothelial differentiation genes (edgs). Wehypothesize that large quantities of LPA and S1P generated by activatedplatelets may influence endothelial cell functions. Using an in vitrowound healing assay, we observed that LPA and S1P stimulated closure ofwounded monolayers of human umbilical vein endothelial cells and adultbovine aortic endothelial cells, which express LPA receptor Edg2, andS1P receptors Edg1 and Edg3. The two major components of wound healing,cell migration and proliferation, were stimulated individually by bothlipids. LPA and S1P also stimulated intracellular Ca²⁺mobilization and mitogen-activated protein kinase (MAPK)phosphorylation. Pertussis toxin partially blocked the effects of bothlipids on endothelial cell migration, MAPK phosphorylation, andCa²⁺ mobilization, implicatingG_i/_o-coupled Edg receptor signaling inendothelial cells. LPA and S1P did not cross-desensitize each other inCa²⁺ responses, suggesting involvement of distinctreceptors. Thus LPA and S1P affect endothelial cell functions throughsignaling pathways activated by distinct GPCRs and may contribute tothe healing of wounded vasculatures.