Background: Aortic aneurysm (AA) dissection and rupture are catastrophic outcomes of aortic disease and major causes of cardiovascular mortality, with no pharmacological therapy to prevent progression. The bioactive lipid sphingosine-1-phosphate (S1P) regulates vascular homeostasis by modulating endothelial integrity, smooth muscle contractility, and inflammation via five G protein-coupled receptors (S1PR1-5). Although dysregulation of S1P signaling is implicated in multiple cardiovascular disorders, its contribution to aneurysm formation, destabilization, and rupture remains unclear.
Methods: Plasma and aneurysmal tissue samples were obtained from patients undergoing elective repair of thoracic (n=15) or abdominal (n=60) aneurysms and compared with healthy controls (n=40). In an independent longitudinal cohort comprising 120 patients from the Magnetic resonance imaging for abdominal aortic aneurysms to predict rupture or surgery (MA³RS) study at the University of Edinburgh, Scotland, UK, serial plasma samples were obtained at baseline and every six months for up to two years, both before and after surgical repair, rupture, or continued surveillance without intervention. Sphingolipids were analysed by LC-MS/MS. Experimental aneurysms were induced in ApoE-deficient mice by Angiotensin II (Ang II; 1000ng/kg/min; 28 days) and combined with S1P lyase inhibitor 4′-deoxypyridoxine (DOP, 4.5mg/kg/day) to elevate S1P. Aneurysm morphology, molecular signatures, and vascular biomechanics were analysed; ApoE/S1PR3-deficient mice delineated receptor-specific effects.
Results: Targeted sphingolipidomic analysis revealed pronounced alterations in the sphingolipid composition of plasma and aneurysmal tissue, distinguishing AA patients from controls. Principal component analysis demonstrated clear separation between groups in both plasma and tissue datasets. Among all detected lipids, S1P emerged as the most significantly upregulated species and the strongest discriminator between AA and control samples, supported by robust diagnostic performance (AUC = 0.90, 95% CI: 0.81-0.96). Quantitative analysis confirmed that plasma S1P concentrations were approximately twofold higher and tissue S1P levels threefold higher in aneurysmal compared with control aortae. In the longitudinal MAR3S cohort, plasma S1P concentrations exhibited a significant inverse correlation with time to rupture or surgical repair, rising progressively as the event approached and declining after intervention. Notably, S1P levels did not correlate with aneurysm diameter, indicating that S1P elevation reflects vascular instability rather than size-dependent remodelling. In mice, pharmacological S1P elevation by DOP markedly increased rupture-related mortality (70%vs.25%; p<0.05) and was associated with reduced aortic elasticity, increased stiffness, and downregulation of VSMC contractile genes via S1P/S1PR3 signaling. ApoE/S1PR3-deficient mice were protected, maintaining aortic integrity and contractile phenotype under elevated S1P.
Conclusion: Human longitudinal data identify S1P as a dynamic biomarker of aneurysm instability that rises preceding rupture or repair and normalizes after surgical intervention, independently of aneurysm size. Experimental data confirm that elevated S1P drives aneurysm progression and rupture through S1PR3-mediated VSMC reprogramming, establishing the S1P/S1PR3 axis as a mechanistic driver and promising therapeutic target.
