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

BACKGROUND Sphingosine 1-phosphate receptor 1 (S1PR1) is a key regulator of vascular homeostasis and immune function, yet its role in atherosclerosis remains controversial because activation of the same receptor produces divergent biological effects across different vascular and immune cell populations. OBJECTIVE This review synthesizes current evidence on the molecular and cellular functions of S1PR1 in atherosclerosis and proposes a context-dependent framework to explain seemingly conflicting experimental findings and guide therapeutic development. METHODS We conducted a narrative review of experimental and translational studies investigating S1PR1 expression, signaling mechanisms, and pharmacological modulation in endothelial cells, macrophages, vascular smooth muscle cells, and animal models of atherosclerosis. RESULTS Evidence consistently indicates that the biological effects of S1PR1 are determined by cell type, ligand presentation, and the surrounding inflammatory environment rather than by receptor activation alone. In endothelial cells, S1PR1 preserves vascular barrier integrity, suppresses nuclear factor-κB signaling, and limits leukocyte recruitment, particularly when activated by apolipoprotein M-bound high-density lipoprotein-associated sphingosine 1-phosphate. In macrophages, S1PR1 promotes anti-inflammatory polarization, cholesterol efflux, efferocytosis, and cell survival through coordinated activation of phosphoinositide 3-kinase/Akt and liver X receptor signaling pathways. In contrast, injury-induced S1PR1 expression in vascular smooth muscle cells promotes proliferation, migration, and neointimal hyperplasia through interleukin-6/signal transducer and activator of transcription 3 signaling. This context-dependent framework also explains the variable efficacy of S1PR1-targeting agents, highlighting the advantages of selective, non-degrading agonists over functional antagonists. However, important translational challenges remain, including differences between murine models and human disease in circulating sphingosine 1-phosphate biology. CONCLUSIONS S1PR1 functions as a context-dependent regulator of atherosclerosis whose effects depend on cellular identity, ligand delivery, and disease stage. Future therapeutic strategies should prioritize cell-selective drug delivery, biased or non-degrading S1PR1 agonists, restoration of apolipoprotein M-mediated signaling, and biomarker-guided patient selection to maximize vascular protection while minimizing adverse remodeling.