Same Receptor, Opposite Fates: Why S1PR1 Cuts Both Ways in Atherosclerosis

Sphingosine 1-phosphate receptor 1, or S1PR1, has long been one of the most tantalising and most confusing targets in vascular medicine. The same receptor that shields arteries from inflammation in one cell type appears to drive destructive vessel remodelling in another, and decades of animal work have produced results that seemed flatly contradictory. A new review published in Artery Research argues that the contradictions are not noise but signal: S1PR1’s effect in atherosclerosis is not a property of the receptor itself, but of the cell that expresses it, the ligand that activates it and the inflammatory environment surrounding it.

The review, authored by Thang Nguyen Ngoc and colleagues and published on 14 October 2026, synthesises evidence across endothelial cells, macrophages and vascular smooth muscle cells, and proposes a context-dependent framework to reconcile the conflicting literature. The authors are careful about the limits of their evidence. They explicitly distinguish in vitro mechanistic studies, murine models and human observational data, and they note that no clinical trial data directly address S1PR1’s role in human atherosclerosis. Existing trials of S1PR1 modulators come almost entirely from non-atherosclerotic indications such as multiple sclerosis, and no direct clinical evidence currently demonstrates that selective S1PR1 agonism reduces human atherosclerotic burden or cardiovascular events.

The molecular biology explains why context matters so much. S1P is a bioactive lysosphingolipid that signals through five G protein-coupled receptors, S1PR1 through 5. S1PR1 couples exclusively to Gi/o pathways, inhibiting adenylyl cyclase and activating PI3K/Akt/Rac signalling, whereas S1PR2 and S1PR3 additionally recruit Gq and G12/13, triggering pro-inflammatory Rho/ROCK and PLC activation. Within the arterial wall, S1PR1 is the dominant endothelial receptor, while S1PR2 and S1PR3 are abundant in vascular smooth muscle cells and plaque macrophages. The baseline vascular phenotype, the authors argue, is dictated by the spatial ratio of these co-expressed subtypes.

Ligand presentation adds another layer of complexity. In plasma, most S1P circulates bound to HDL via apolipoprotein M, and this ApoM-HDL-S1P axis has been proposed as a major mediator of HDL’s cardiovascular protective properties. ApoM-bound HDL-S1P stabilises a cell-surface S1PR1-beta-arrestin 2 complex and preferentially suppresses NF-kappaB without extensive receptor internalisation. Albumin-bound S1P at the same concentration produces greater Gi activation and receptor endocytosis but lacks the same anti-inflammatory effect. The same biased pattern was reported independently in foetal placental endothelium, where HDL-S1P, but not albumin-S1P, suppressed TNF-alpha-induced VCAM-1, ICAM-1, E-selectin, MCP-1 and IL-8, an effect reversed by the S1PR1 antagonist W146. The structural basis for this selectivity remains unresolved and should be regarded as a working model, the authors caution.

In endothelial cells, S1PR1 emerges as a vascular guardian. Galvani and colleagues showed that endothelial S1PR1 deletion accelerated aortic lesion formation in ApoE-deficient mice through amplified ICAM-1 expression, while overexpression attenuated it. Mechanistically, S1PR1 suppresses NF-kappaB largely via Gi/o-PI3K-eNOS-nitric oxide signalling, restraining the adhesion molecules and chemokines that drive monocyte recruitment and plaque initiation. The receptor also cooperates with S1PR3 to mediate S1P-induced vasodilation in human resistance arterioles, and S1PR1 mediates eNOS-dependent inhibition of monocyte adhesion in mouse models. A notable exception underscores the context-dependence: in human lymphatic endothelial cells, S1PR1 activates rather than suppresses NF-kappaB, promoting lymphangiogenesis, though subsequent work suggests lymphatic S1PR1 may also facilitate inflammatory resolution by promoting macrophage clearance through ERK-CCL2 signalling. The authors stress that direct evidence linking lymphatic S1PR1 to plaque regression remains limited.

In macrophages, the picture is strikingly atheroprotective. Gonzalez and colleagues showed, via bone marrow transplant into LDLR-knockout mice, that myeloid-specific S1PR1 knockout accelerated atherosclerosis at nine weeks, an effect less apparent by twelve weeks. Conversely, myeloid S1PR1 overexpression reduced lesion area by roughly 50 percent in the aortic root and about 90 percent in the brachiocephalic artery. Transcriptional profiling revealed a programme absent from classical M1/M2 polarisation: Gi-mediated PKA suppression de-represses PU.1 and IRF8 to upregulate anti-inflammatory genes, while an AKT1-mTORC1-LXRalpha axis upregulates ABCA1, ABCG1 and MerTK, simultaneously resolving inflammation, promoting cholesterol efflux and enhancing efferocytosis. The agonist KRP-203-phosphate reproduced this signature pharmacologically, suggesting the phenotype is agonist-inducible rather than an artefact of genetic overexpression.

A key structural element is the SR-B1/S1PR1 complex. Bassila and colleagues detected this complex, at sub-40-nanometre proximity, in plaque foam cells of S1pr1-eGFP knockin/ApoE-deficient mice, and in vivo administration of the antagonist Ex26 reduced the signal to background, indicating that active receptor signalling, not mere receptor presence, sustains the complex. Disrupting the association reduced HDL-mediated cholesterol efflux by roughly 40 percent and eliminated its anti-apoptotic effect. This is, according to the review, the only in vivo evidence for active S1PR1 signalling within plaque macrophages, anchoring extensive cell culture data within the disease context.

In vascular smooth muscle cells, the same receptor tells the opposite story. Kitano and colleagues identified S1PR1 as the dominant injury-responsive S1P receptor in VSMCs: expression was selectively upregulated in carotid neointima after ligation while S1PR2 and S1PR3 remained unchanged or decreased. VSMC-specific S1PR1 overexpression enhanced neointimal hyperplasia, proliferation and expression of PDGF-B, EGR-1 and IL-6, and IL-6 neutralisation abolished neointima formation entirely, pointing to an S1PR1-IL-6-JAK/STAT3 axis as a major driver of injury-induced remodelling. At least four distinct upstream pathways converge on S1PR1 induction in VSMCs, including oxidative stress, Wnt/beta-catenin-TCF4 transcriptional activation, angiotensin II signalling and diabetic metabolic conditions. However, the authors note that S1PR1’s independent contribution cannot be confirmed from these studies, since the phenotype could reflect a shift in the receptor ratio rather than S1PR1 specifically.

Human expression data add a translational wrinkle. Liu and colleagues found S1PR1-positive cell density 27-fold higher in maximally diseased, foam cell-rich regions of femoral endarterectomy specimens than in minimally diseased plaque. Yet patients with coronary artery disease show lower plasma S1P and HDL-S1P than controls, while ApoE-deficient mice have elevated plasma S1P due to impaired ApoE-mediated LDL receptor clearance. This species difference means increased S1PR1 expression in human lesions may occur in the context of altered or potentially reduced ligand availability, complicating direct extrapolation from murine models.

The pharmacology fits the framework. FTY720 (fingolimod), a functional antagonist that induces receptor degradation, reduced lesion area by roughly 62.5 percent in LDLR-deficient mice on a high-cholesterol diet and 30 to 40 percent in ApoE-deficient mice, but produced no lesion reduction in a moderate-diet model despite comparable lymphopenia. CYM5442 likewise failed to reduce lesion area in the moderate-diet model despite clear biological activity, indicating that lymphocyte sequestration and reduced systemic inflammatory markers do not reliably predict reduced plaque burden. KRP-203, a selective agonist, reduced aortic root lesion area in LDLR-deficient mice on a cholesterol-rich diet, though it caused persistent lymphopenia. SEW2871, which appears selective and non-degrading, reduced macrophage apoptosis and promotes SR-B1/S1PR1 complex formation, but its efficacy on plaque burden has not been tested in a direct atherosclerotic lesion model. The authors propose, as hypotheses for future study rather than established directions, cell-selective delivery, non-degrading agonists, ApoM-mimetic approaches and S1PR1 PET imaging for biomarker-guided patient selection, while acknowledging that whether this murine context-dependency translates to human vascular disease remains an open question.

Subject of Research: The context- and cell-dependent roles of the sphingosine 1-phosphate receptor 1 in atherosclerosis

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

Article References: Ngoc, T. N., Hsu, S.-C., Chen, C.-L., Duong, C., Vu, T., Hoang, S., Nguyen, Q., Bui, A. T. T., Nguyen, C., & Tran, B. (2026). Context- and Cell-Dependent Roles of S1PR1 in Atherosclerosis: Therapeutic Implications of Selective S1PR1 Modulation. Artery Research, 32(1), Article 44. https://doi.org/10.1007/s44200-026-00143-w

Image Credits: AI Generated

DOI: 10.1007/s44200-026-00143-w

Keywords: S1PR1, sphingosine 1-phosphate, atherosclerosis, endothelial cells, macrophages, vascular smooth muscle cells, HDL, ApoM, fingolimod, SEW2871, neointimal hyperplasia, review