HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation

The sphingosine 1-phosphate receptor 1 (S1P(1)) is abundant in endothelial cells, where it regulates vascular development and microvascular barrier function. In investigating the role of endothelial cell S1P(1) in adult mice, we found that the endothelial S1P(1) 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 S1P(1) 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 S1P(1) 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 S1P(1)-beta-arrestin 2 complex and attenuated the ability of the proinflammatory cytokine TNF alpha to activate NF-kappa B and increase ICAM-1 abundance. Although S1P bound to either chaperone induced MAPK activation, albumin-S1P triggered greater G(i) 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 S1P(1) inhibits vascular inflammation, which may partially explain the cardiovascular protective functions of HDL.