Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation - Novel role for hyaluronan and CD44 receptor family

被引:149
作者
Singleton, Patrick A. [1 ]
Dudek, Steven M. [1 ]
Ma, Shwu-Fan [1 ]
Garcia, Joe G. N. [1 ]
机构
[1] Univ Chicago, Pritzker Sch Med, Dept Med, Chicago, IL 60637 USA
关键词
CELL-ADHESION; IP3; RECEPTOR; LIPID RAFTS; KINASE; ENHANCEMENT; EXPRESSION; TISSUE; ACID; RHO; SPHINGOSINE-1-PHOSPHATE;
D O I
10.1074/jbc.M603680200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The role for hyaluronan (HA) and CD44 in vascular barrier regulation is unknown. We examined high and low molecular weight HA (HMW-HA, similar to 1,000 kDa; LMW- HA, similar to 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 (S1P(1)) 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 S1P(3) 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 S1P(3), 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.
引用
收藏
页码:34381 / 34393
页数:13
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