S1P in the development of atherosclerosis: roles of hemodynamic wall shear stress and endothelial permeability

Atherosclerosis is characterized by focal accumulations of lipid within the arterial wall, thought to arise from effects of hemodynamic wall shear stress (WSS) on endothelial permeability. Identifying pathways that mediate the effects of shear on permeability could therefore provide new therapeutic opportunities. Here, we consider whether the sphingosine-1-phosphate (S1P) pathway could constitute such a route. We review effects of S1P in endothelial barrier function, the influence of WSS on S1P production and signaling, the results of trials investigating S1P in experimental atherosclerosis in mice, and associations between S1P levels and cardiovascular disease in humans. Although it seems clear that S1P reduces endothelial permeability and responds to WSS, the evidence that it influences atherosclerosis is equivocal. The effects of specifically pro- and anti-atherosclerotic WSS profiles on the S1P pathway require investigation, as do influences of S1P on the vesicular pathways likely to dominate low-density lipoprotein transport across endothelium.