Context- and Cell-Dependent Roles of S1PR1 in Atherosclerosis: Therapeutic Implications of Selective S1PR1 Modulation

Abstract Sphingosine 1-phosphate receptor 1 (S1PR1) regulates vascular homeostasis and immune function, but its role in atherosclerosis has remained controversial because activating the same receptor produces divergent effects across cell types. This review synthesizes evidence on S1PR1 signaling in endothelial cells, macrophages, and vascular smooth muscle cells, and proposes a context-dependent framework, shaped by cell type, ligand presentation, and inflammatory environment, to reconcile these conflicting findings. In endothelial cells, S1PR1 preserves barrier integrity and limits leukocyte recruitment when activated by ApoM-bound HDL-S1P. In macrophages, it promotes anti-inflammatory polarization, cholesterol efflux, and efferocytosis via PI3K/Akt and LXR signaling. In vascular smooth muscle cells, by contrast, injury-induced S1PR1 drives proliferation and neointimal hyperplasia through IL-6/STAT3 signaling. This framework also explains the variable efficacy of S1PR1-targeting drugs, favoring selective, non-degrading agonists over functional antagonists, though murine-to-human differences in circulating S1P biology remain a key translational barrier. Future therapeutic strategies should prioritize cell-selective delivery, biased or non-degrading agonists, restoration of ApoM-mediated signaling, and biomarker-guided patient selection to maximize vascular protection while avoiding adverse remodeling.