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Involvement of proteinase activated receptor-2 in the vascular response to sphingosine 1-phosphate.
- Source :
-
Clinical science (London, England : 1979) [Clin Sci (Lond)] 2014 Apr; Vol. 126 (8), pp. 545-56. - Publication Year :
- 2014
-
Abstract
- S1P (sphingosine 1-phosphate) represents one of the key latest additions to the list of vasoactive substances that modulate vascular tone. PAR-2 (proteinase activated receptor-2) has been shown to be involved in cardiovascular function. In the present study, we investigated the involvement of PAR-2 in S1P-induced effect on vascular tone. The present study has been performed by using isolated mouse aortas. Both S1P and PAR-2 agonists induced endothelium-dependent vasorelaxation. L-NAME (N(G)-nitro-L-arginine methyl ester) and wortmannin abrogated the S1P-induced vasorelaxatioin, while significantly inhibiting the PAR-2-mediated effect. Either ENMD1068, a PAR-2 antagonist, or gabexate, a serine protease inhibitor, significantly inhibited S1P-induced vasorelaxation. Aortic tissues harvested from mice overexpressing PAR-2 displayed a significant increase in vascular response to S1P as opposed to PAR-2-null mice. Immunoprecipitation and immunofluorescence studies demonstrated that S1P(1) interacted with PAR-2 and co-localized with PAR-2 on the vascular endothelial surface. Furthermore, S1P administration to vascular tissues triggered PAR-2 mobilization from the plasma membrane to the perinuclear area; S1P-induced translocation of PAR-2 was abrogated when aortic rings were pre-treated with ENMD1068 or when caveolae dysfunction occurred. Similarly, experiments performed in cultured endothelial cells (human umbilical vein endothelial cells) showed a co-localization of S1P(1) and PAR2, as well as the ability of S1P to induce PAR-2 trafficking. Our results suggest that S1P induces endothelium-dependent vasorelaxation mainly through S1P(1) and involves PAR-2 transactivation.
- Subjects :
- Androstadienes
Animals
Aorta metabolism
Aorta physiology
Blotting, Western
Cells, Cultured
Endothelium, Vascular cytology
Endothelium, Vascular metabolism
Endothelium, Vascular physiology
Gabexate pharmacology
Human Umbilical Vein Endothelial Cells drug effects
Human Umbilical Vein Endothelial Cells metabolism
Humans
In Vitro Techniques
Male
Mice
Mice, Knockout
Mice, Transgenic
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide Synthase antagonists & inhibitors
Nitric Oxide Synthase metabolism
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Piperazines pharmacology
Protein Transport drug effects
Receptor, PAR-2 antagonists & inhibitors
Receptor, PAR-2 genetics
Receptors, Lysosphingolipid metabolism
Serine Proteinase Inhibitors pharmacology
Sphingosine pharmacology
Vasodilation genetics
Vasodilation physiology
Wortmannin
Aorta drug effects
Lysophospholipids pharmacology
Receptor, PAR-2 metabolism
Sphingosine analogs & derivatives
Vasodilation drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8736
- Volume :
- 126
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Clinical science (London, England : 1979)
- Publication Type :
- Academic Journal
- Accession number :
- 24131465
- Full Text :
- https://doi.org/10.1042/CS20130272