Abstract 067: Endothelial S1P/S1P1 Signaling is Critical Regulator of Blood Flow and Pressure
Background and objectives: Sphingosine-1-phosphate (S1P) is emerging as a pivotal signaling molecule within the vasculature. S1P has been known as a potent endothelial nitric oxide synthase activator through G-protein coupled receptor S1P1 and less abundant S1P3 on endothelial cells (EC). Although it has been recently shown that S1P/S1P1 signaling mediates EC alignment in response to flow, the role of S1P1 signaling in the pathogenesis of hypertension remains unknown. FTY720, an S1P1 functional antagonist, recently approved by the FDA to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo. Thus, the aim of this study is to investigate whether S1P-S1P1 signaling pathway is crucial in blood flow and pressure regulation.
Methods: The BP was evaluated in conscious mice with tail cuff system, whereas the vascular reactivity was examined with pressure myograph system in mesenteric arteries isolated from age matched WT and EC-S1P1-/- mice. Results. Here we report for the first time that S1P1-mediated signaling protects from hypertension. Administration of SEW 2871, an agonist of S1P1, to angiotensin-II-induced hypertensive mice lowered blood pressure to normotensive levels (110.7±3.1 vs. 160.7±2.4 mmHg, SEW 2871 vs. vehicle respectively). Pharmacological inhibition of S1P1 with W146 (100 nM and 1 μM) markedly reduced flow-induced vasodilation (Emax 25.2±3.8 and 2.5±2.3 vs. 48.6±4.9 μm, W146 100 nM and 1μM respectively vs. WT). These data were corroborated by using a genetic approach: mice EC-S1P1-/- were hypertensive (124.7±1.9 vs. 109±1.7 mmHg, EC-S1P1-/- vs. S1P1f/f mice) and showed a reduced response to flow-induced vasodilation (Emax 15.2±3.0 vs. 53.8±5.0 μm, EC-S1P1-/- vs. S1P1f/f mice mesenteric artery).
Conclusion: Our study identifies S1P-S1P1 signaling as a new regulatory pathway of blood flow and pressure homeostasis, providing a novel therapeutic target for the treatment of hypertension.
Author Disclosures: A. Cantalupo: None. C. Liu: None. T. Hla: None. A. Di Lorenzo: None. E. Dautaj: None.
- © 2015 by American Heart Association, Inc.