Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation

Novel role for hyaluronan and CD44 receptor family

Patrick A. Singleton, Steven M. Dudek, Shwu Fan Ma, Joe GN Garcia

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

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-HAinduced 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.

Original languageEnglish (US)
Pages (from-to)34381-34393
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number45
DOIs
StatePublished - Nov 10 2006
Externally publishedYes

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CD44 Antigens
Lysosphingolipid Receptors
Hyaluronic Acid
Transcriptional Activation
Blood Vessels
Acoustic impedance
Electric Impedance
Monolayers
Protein Isoforms
Phosphorylation
Association reactions
Caveolins
Lipids
Blocking Antibodies
Cytoskeleton
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry

Cite this

Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation : Novel role for hyaluronan and CD44 receptor family. / Singleton, Patrick A.; Dudek, Steven M.; Ma, Shwu Fan; Garcia, Joe GN.

In: Journal of Biological Chemistry, Vol. 281, No. 45, 10.11.2006, p. 34381-34393.

Research output: Contribution to journalArticle

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