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J. Biol. Chem., Vol. 281, Issue 45, 34381-34393, November 10, 2006

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Transactivation of Sphingosine 1-Phosphate Receptors Is Essential for Vascular Barrier Regulation

NOVEL ROLE FOR HYALURONAN AND CD44 RECEPTOR FAMILY^*

From the Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637

The role for hyaluronan (HA) and CD44 in vascular barrier regulation is unknown. We examined high and low molecular weight HA (HMW-HA, 1,000 kDa; LMW-HA, 2.5 kDa) effects on human transendothelial monolayer electrical resistance (TER). HMW-HA increased TER, whereas LMW-HA induced biphasic TER changes ultimately resulting in EC barrier disruption. HMW-HA induced the association of the CD44s isoform with, and AKT-mediated phosphorylation of, the barrier-promoting sphingosine 1-phosphate receptor (S1P₁) within caveolin-enriched lipid raft microdomains, whereas LMW-HA induced brief CD44s association with S1P₁ followed by sustained association of the CD44v10 isoform with, and Src and ROCK 1/2-mediated phosphorylation of, the barrier-disrupting S1P₃ receptor. HA-induced EC cytoskeletal reorganization and TER alterations were abolished by either disruption of lipid raft formation, CD44 blocking antibody or siRNA-mediated reductions in expression of CD44 isoforms. Silencing S1P₁, AKT1, or Rac1 blocked the barrier enhancing effects of HA whereas silencing S1P₃, Src, ROCK1/2, or RhoA blocked the barrier disruption induced by LMW-HA. In summary, HA regulates EC barrier function through novel differential CD44 isoform interaction with S1P receptors, S1P receptor transactivation, and RhoA/Rac1 signaling to the EC cytoskeleton.

Received for publication, April 17, 2006 , and in revised form, September 7, 2006.

^* This research was supported by the Ruth L. Kirschstein National Research Service Award National Institutes of Health F32 HL68472. 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 Medicine, University of Chicago Pritzker School of Medicine, 5841 S. Maryland Ave., W604, Chicago, IL 60637. E-mail: jgarcia{at}medicine.bsd.uchicago.edu.

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