https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Düsseldorf Institut für Molekulare Medizin III Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 3Universitätsklinikum Essen Institut für Pathophysiologie Essen, Deutschland; 4Universitätsklinikum Düsseldorf Gefäß- und Endovaskularchirurgie Düsseldorf, Deutschland; 5Universitätsklinikum Düsseldorf Klinik für Herzchirurgie Düsseldorf, Deutschland; 6Universitätsklinikum Essen Sektion Gefäßchirurgie und Endovaskuläre Chirurgie Essen, Deutschland
Background: The bioactive lipid mediator Sphingosine-1-phosphate (S1P) regulates blood pressure, the stabilization of endothelial barrier and vascular smooth muscle cells (VSMCs) via highly selective G-protein-coupled receptors (S1PR1-5). In experimental studies, augmented plasma S1P levels have been linked to several cardiovascular diseases, including stroke, heart failure, atherosclerosis, and hypertension. Aortic aneurysm is a life-threatening condition due to a high risk of rupture, with no available pharmacological treatments to stabilize or reverse disease progression. Our study investigated the causal involvement of S1P modulation in aneurysm development and rupture.
Hypothesis: Pharmacologic enhancement of S1P level leads to AA progression and subsequent rupture in a mouse model of angiotensin II (Ang II)-induced AA formation.
Methods: Human tissue and plasma samples were obtained from patients with thoracic or abdominal AA undergoing surgery or healthy subjects. AA formation was induced by the administration of Ang II via osmotic pumps (1000 ng/kg/min) for 28 days in apolipoprotein E (ApoE) - deficient mice fed a high cholesterol diet with or without oral administration of the S1P lyase inhibitor 4′-deoxypyridoxine (DOP; 4.5 mg/kg/d). AA incidence, morphological classification, and gene expression were assessed through histopathology, immunostaining, and real-time PCR. Vasoreactivity and tension studies were conducted on aortic segments using a small vessel myograph. Blood pressure was measured via tail-cuff method. Sphingolipidomics were implemented by LC-MS/MS.
Results: In a selected group of human patients suffering from thoracic (n=15) and abdominal aortic aneurysms (n=60) undergoing invasive surgery, we observed 2-fold higher plasma and 3-fold higher aneurysmatic tissue S1P levels compared to controls (n=20). Raising S1P levels by DOP treatment in ApoE-/- mice receiving AngII infusions led to a dramatic increase in mortality (75% versus 25%; p<0.05) due to aneurysm rupture as evidenced by massive blood clots in the thorax or abdomen. This treatment also induced dissecting aneurysms, caused intramural hematomas and increased elastic breaks, shifting AA to more severe forms. DOP-treated aortae exhibited reduced elasticity, hypercontractility and increased stiffness, which correlated with downregulated VSMC genes (ACTA2, SM-MHC, SM22a), a hallmark of aneurysmatic disease in mice and humans.
Conclusion: AA patients exhibit higher plasma and aortic tissue S1P concentrations. Monitoring plasma S1P may constitute a novel biomarker that helps identify patients at risk of AA progression. In mice, pharmacological raising of S1P promotes AA formation possibly by altering arterial biomechanics. Pharmacological targeting of S1P may constitute a novel approach to prevent AA progression and stabilize existing AAs.