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1 Department of Cardiovascular Physiology, Kagawa University Faculty of Medicine, Kita-Gun, Kagawa, Japan
2 Department of Dermatology, Kagawa University Faculty of Medicine, Kita-gun, Kagawa, Japan
* To whom correspondence should be addressed. E-mail: igarashi{at}med.kagawa-u.ac.jp.
Sphingosine 1-phosphate (S1P) is a platelet-derived angiogenic lipid growth factor, modulating G-protein coupled S1P1 receptors (S1P1-R) to activate endothelial NO synthase (eNOS) as well as MAP kinase pathways in endothelial cells. We explored whether and how hydrogen peroxide (H2O2), a representative reactive oxygen species (ROS), alters S1P1-R expression and influences S1P signaling in cultured bovine aortic endothelial cells (BAEC). When BAEC are treated with pathophysiologically relevant concentration of H2O2 (150 µM for 30 minutes), S1P1-R protein expression levels are acutely augmented by ~30 folds in a dose-dependent fashion. When BAEC have been pre-treated with H2O2, subsequent S1P stimulaion (100 nM) leads to higher degree of eNOS enzyme activation (assessed as i[cGMP], 1.7 ± 0.2 folds vs. no H2O2 pretreatment groups, p<0.05), associated with higher magnitude of phosphorylation responses of eNOS as well as of MAP kinases ERK1/2. An inhibitor of Src-family tyrosine kinase PP2 abolished the effects of H2O2 on both S1P1-R protein up-regulation and enhanced BAEC responses to S1P. H2O2 does not augment S1P1 mRNA expression, while vascular endothelial growth factor under identical cultures leads to increases in S1P1-R mRNA signals. While H2O2 attenuates proliferation of BAEC, addition of S1P restores growth responses of these cells. These results demonstrate that extracellularly administered H2O2 increases S1P1-R expression and promotes endothelial responses for subsequent S1P treatment. These results may identify potentially important point of cross-talk between ROS and sphingolipid pathways in vascular responses.
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