Abstract 069: Local and Circulating Sphingosine-1-Phosphate in Blood Pressure Regulation

Abstract

Sphingosine-1-phosphate (S1P), a bioactive lipid, regulates different biological processes in health and disease. Once synthetized, endothelial S1P is transported outside the cells via Spinster-2 (Spns-2), and can signal mainly through the sphingosine-1-phosphate receptor-1 (S1P1) in autocrine/paracrine manner. Alternatively, S1P can bind circulating carriers, including ApoM of HDL or albumin. Recently, we reported a key role of endothelial S1P-S1P1 autocrine signaling in vascular function and blood pressure (BP) homeostasis. To dissect the contribution of endothelium-derived S1P versus circulating HDL-bound S1P on BP regulation, we used ApoM knockout mice (ApoM-/-) and developed mice lacking the endothelial Spinster-2 (ECKO-Spns2). At baseline, systolic BP (SBP) was markedly increased in both ECKO-Spns2 (120.8± 2.1 vs. 106.6±1.3 mmHg, n=8) and ApoM-/- (122.6±1.0 vs. 109.0±1.4 mmHg, n=8) vs control mice. Vasodilation of mesenteric arteries (MA) to acetylcholine was preserved in both mouse models, whereas flow-induced vasodilation was significantly reduced in ECKO-Spns2 (Emax 36.0±1.5 vs. 53.6±3.6 % vasodilation, n=5) but not in ApoM-/- MA, suggesting that autocrine S1P signaling requires the S1P transporter Spns-2. However, both ECKO-Spns2 and ApoM-/- showed a reduced NO production compared to control MA. Moreover, chronic infusion of AngII resulted in higher BP in ECKO-Spns2 (156.0± 1.2 vs. 142.0±1.6 mmHg, n=8) and ApoM-/- (158.5±1.1 vs. 144.1±1.3 mmHg, n=8) vs control mice. Interestingly, chronic AngII strongly reduced vasodilation in response to flow in both ECKO-Spns2 (Emax 19.3±2.5 vs. 35.4±7.1 % vasodilation, n=5) and ApoM-/- (Emax 22.9±1.1 vs. 34.8±6.8 % vasodilation, n=5) compared to control MA, suggesting a protective role of local and circulating S1P. Additionally, basal NO production was further impaired by the AngII infusion (ECKO-Spns2 -32.7% and ApoM-/- -42.8%, vs control MA), confirming the pivotal role of S1P-S1P1-NO pathway in vascular and BP homeostasis.