HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P ₁ to limit vascular inflammation

Abstract

The sphingosine 1-phosphate receptor 1 (S1P1) is abundant in endothelial cells, where it regulates vascular development and microvascular barrier function. In investigating the role of endothelial cell S1P1 in adult mice, we found that the endothelial S1P1 signal was enhanced in regions of the arterial vasculature experiencing inflammation. The abundance of proinflammatory adhesion proteins, such as ICAM-1, was enhanced in mice with endothelial cell–specific deletion of S1pr1 and suppressed in mice with endothelial cell–specific overexpression of S1pr1, suggesting a protective function of S1P1 in vascular disease. The chaperones ApoM+HDL (HDL) or albumin bind to sphingosine 1-phosphate (S1P) in the circulation; therefore, we tested the effects of S1P bound to each chaperone on S1P1 signaling in cultured human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs to ApoM+HDL-S1P, but not to albumin-S1P, promoted the formation of a cell surface S1P1–β-arrestin 2 complex and attenuated the ability of the proinflammatory cytokine TNFα to activate NF-κB and increase ICAM-1 abundance. Although S1P bound to either chaperone induced MAPK activation, albumin-S1P triggered greater Gi activation and receptor endocytosis. Endothelial cell–specific deletion of S1pr1 in the hypercholesterolemic Apoe−/− mouse model of atherosclerosis enhanced atherosclerotic lesion formation in the descending aorta. We propose that the ability of ApoM+HDL to act as a biased agonist on S1P1 inhibits vascular inflammation, which may partially explain the cardiovascular protective functions of HDL.

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

“…Mice were housed in individual ventilated cages in a temperature-controlled facility with a 12-h light/dark cycle at Weill Cornell Medical College. EC-specific S1pr1 knockout mice (S1pr1 flox/flox Cdh5-Cre-ER T2 ; S1pr1 iECKO ) were generated as described (12,13,16,17). Mice were treated with tamoxifen by oral gavage (50 μg/d) for the first 3 d after birth and used for the experiments at the age of 10-16 wk.…”

“…Cdh5-Cre-ER T2 ; referred to as S1pr1 iECKO ) (12,(15)(16)(17). Mice were treated with tamoxifen for the first 3 d after birth and allowed to develop into adulthood.…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…112,113 Of note, at least some functions of S1P appear to be only exerted if S1P is present on HDL. 107 This is of note because only about 50% of S1P in plasma is transported by HDL. The rest is transported by albumin (about 30%) and apoB-containing lipoproteins.…”

S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization

“…It has been recently suggested that S1P bound to ApoM-containing HDL activates endothelial S1PR1 and results in a suppression of inflammatory responses (53). Although the structure of the ApoM protein supports the binding of S1P and HDL-associated S1P is bound specifically to ApoM such that ApoM-containing HDL contain S1P, whereas HDL devoid of ApoM do not (52), Sattler et al (54) have clearly demonstrated that S1P can be loaded in vitro or in vivo onto HDL, which are virtually absent of ApoM, and restore the defective signaling of the HDLs.…”

“…Clearly, the role of lipoprotein ApoM in the transfer of S1P in lipoproteins onto cell S1P receptors remains to be determined. It has been further suggested that apoM-containing HDL engage endothelial S1P1 to form a signaling complex with -arrestin 2 that suppresses nuclear factor B-dependent inflammatory pathways (53). In another recent study, it was shown that HDL from patients with mild coronary artery disease contains 5-fold less S1P concentration than HDL from healthy individuals (54) and that the S1P-deficient HDL is less efficient in activating endothelial molecular pathways.…”