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J. Biol. Chem., Vol. 283, Issue 36, 25074-25081, September 5, 2008

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High Density Lipoprotein-associated Sphingosine 1-Phosphate Promotes Endothelial Barrier Function^*

From the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425

High density lipoproteins (HDL) are major plasma carriers of sphingosine 1-phosphate (S1P). Here we show that HDL increases endothelial barrier integrity as measured by electric cell substrate impedance sensing. S1P was implicated as the mediator in this process through findings showing that pertussis toxin, an inhibitor of G_i-coupled S1P receptors, as well as antagonists of the S1P receptor, S1P1, inhibited barrier enhancement by HDL. Additional findings show that HDL stimulates endothelial cell activation of Erk1/2 and Akt, signaling pathway intermediates that have been implicated in S1P-dependent endothelial barrier activity. HDL was also found to promote endothelial cell motility, a process that may also relate to endothelial barrier function in the context of a vascular injury response. The effects of HDL on endothelial cell Erk1/2 and Akt activation and motility were suppressed by pertussis toxin and S1P1 antagonists. However, both HDL-induced barrier enhancement and HDL-induced motility showed a greater dependence on Akt activation as compared with Erk1/2 activation. Together, the findings indicate that HDL has endothelial barrier promoting activities, which are attributable to its S1P component and signaling through the S1P1/Akt pathway.

Received for publication, February 14, 2008 , and in revised form, June 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL80404 and RR107677 (to K. M. A.), HL52813 (to W. S. A.), and HL079274 (to S. M. H.). This work was also supported by American Heart Association-Jon DeHaan Foundation Scientist Development Grant in Angiogenesis 0230245N (to K. M. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cell Biology and Anatomy, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-3535; Fax: 843-792-0664; E-mail: argravek{at}musc.edu.

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