Sphingosine-1-phosphate -receptor 3 (S1PR3) signaling in vascular smooth muscle cells as a target to stabilize aortic aneurysm and dissection

Nathalie Schröder (Düsseldorf)1, D.-A. Duse (Düsseldorf)2, P. Wollnitzke (Düsseldorf)1, W. Ibing (Düsseldorf)3, M. Lainka (Essen)4, H. Schelzig (Düsseldorf)3, B. Levkau (Düsseldorf)1

1Universitätsklinikum Düsseldorf Institut für Molekulare Medizin III Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 3Universitätsklinikum Düsseldorf Klinik für Kardiovaskuläre Chirurgie Düsseldorf, Deutschland; 4Universitätsklinikum Essen Klinik für Thorax- und Kardiovaskuläre Chirurgie Essen, Deutschland


Background: The bioactive lipid mediator Sphingosine-1-phosphate (S1P) affects the regulation of blood pressure, stabilization of endothelial barriers and vascular smooth muscle cells (VSMCs) via highly selective G-protein-coupled receptors (S1PR1-5). Notably, a differential expression of S1PRs was discovered in human abdominal aortic aneurysms (AA). Aortic aneurysm is a life-threatening condition stemming from a complicated interplay between genetic, local, and environmental factors. At present, there is no pharmacological remedy to stabilize and avert the rupturing of AA.

Hypothesis: Deregulated signaling of S1P/S1PR3 induces a novel contraction vasculopathy leading to AA rupture and progression.

Methods: 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 or ApoE x S1PR3 double mutant mice fed a high-cholesterol diet. 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 over the entire experimental set-up. Sphingolipidomics were implemented by LC-MS/MS on mouse and human tissue and plasma samples.

Results: A clear increase in survival was observed in ApoE x S1PR3 double knockout mice compared to the ApoE group over 28 days under Ang II infusion (95% versus 70%; p<0.05). Additionally, histological examination of the arterial wall showed fewer elastic breaks. Passive tension studies demonstrated an increased elasticity. Furthermore, vasoreactivity studies of 2 mm aortic segments indicated a reduced vasoactive response to phenylephrine and Ang II in ApoE x S1PR3 double mutant mice compared to ApoE. Additionally, the expression of VSMC differentiation and contractile genes was substantially higher in ApoE x S1PR3 double mutant mice indicating resistance phenotypic switch. In a selected group of human AA patients undergoing invasive surgery, we observed lower plasma and higher aneurysm S1P levels compared to control aortic tissue. Currently, we are investigating if pharmacological inhibition of S1P/S1PR3 signaling could prevent aneurysm formation and rupture.

Conclusion: Tonic S1PR3 signaling may play a role in the pathogenesis and dissection of AA by altering arterial biomechanics and expression of VSMC contractility genes. Pharmacological targeting of the S1P/S1PR3 axis may constitute a novel approach to preventing progression and/or stabilizing existing AAs.

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