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S1P Carrier-Dependent Regulation of Endothelial Barrier: HDL-S1P Prolongs Endothelial Barrier Enhancement as Compared to Albumin-S1P Via Effects on Levels, Trafficking and Signaling of S1P1.

J Biol Chem. 2012 Nov 7;

Authors: Wilkerson BA, Grass GD, Wing SB, Argraves WS, Argraves KM


Sphingosine-1-phosphate (S1P) is a blood borne lysosphingolipid that acts to promote endothelial cell (EC) barrier function. In plasma, S1P is associated with both high density lipoproteins (HDL) and albumin, but it is not known whether the carriers impart different effects on S1P signaling. Here we establish that HDL-S1P sustains EC barrier longer than albumin-S1P. We showed that the sustained barrier effects of HDL-S1P are dependent on signaling by the S1P receptor, S1P1, and involve persistent activation of Akt and eNOS, as well as activity of the downstream NO target, soluble guanylate cyclase (sGC). Total S1P1 protein levels were found to be higher in response to HDL-S1P treatment as compared to albumin-S1P, and this effect was not associated with increased S1P1 mRNA or dependent on de novo protein synthesis. Several pieces of evidence indicate that long term EC barrier enhancement activity of HDL-S1P is due to specific effects on S1P1 trafficking. First, the rate of S1P1 degradation, which is proteasome mediated, was slower in HDL-S1P treated cells as compared to cells treated with albumin-S1P. Second, the long-term barrier promoting effects of HDL-S1P were abrogated by treatment with the recycling blocker, monensin. Finally, cell surface levels of S1P1 and levels of S1P1 in caveolin-enriched microdomains were higher after treatment with HDL-S1P compared to albumin-S1P. Together, the findings reveal S1P carrier-specific effects on S1P1 and point to HDL as the physiological mediator of sustained S1P1-PI3K-Akt-eNOS-sGC-dependent EC barrier function.

PMID: 23135269 [PubMed - as supplied by publisher]