The role of sphingosine-1-phosphate in endothelial barrier function

Abstract

Loss of endothelial barrier function is implicated in the etiology of metastasis, atherosclerosis, sepsis and many other diseases. Studies suggest that sphingosine-1-phosphate (S1P), particularly HDL-bound S1P (HDL-S1P) is essential for endothelial barrier homeostasis and that HDL-S1P may be protective against the loss of endothelial barrier function in disease. This review summarizes evidence providing mechanistic insights into how S1P maintains endothelial barrier function, highlighting the recent findings that implicate the major S1P carrier, HDL, in the maintenance of the persistent S1P-signaling needed to maintain endothelial barrier function. We review the mechanisms proposed for HDL maintenance of persistent S1P-signaling, the evidence supporting these mechanisms and the remaining fundamental questions.

Keywords: Endothelial barrier function; HDL; S1P; Sphingosine-1-phosphate.

Figure 1. S1P/S1PR1-signaling

In response to S1P, the S1PR1 signaling pathway may increase endothelial barrier function by stimulating actin-dependent outward spreading of endothelial cells and suppressing cellular contractility. Arrows, induction; bar-headed lines, inhibition.

Figure 2. Hypothetical mechanism for greater S1PR1 recycling in response to HDL–S1P

Following activation of S1PR1 by albumin–S1P or HDL–S1P, S1PR1 is targeted for internalization and degradation by the proteasome. We speculate that HDL recruits factors such as NHERF-2 to the S1PR1 complex, thereby targeting S1PR1 to recycling endosomes. HDL might induce recruitment of such factors in S1PR1 recycling through its lipid transport activity. To contrast the mechanistic insights supported by experimental evidence with our speculations, we identify the components of our hypothetical mechanism by asterisks.