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Involvement of proteinase activated receptor-2 in the vascular response to sphingosine 1-phosphate.

Clinical science (London, England : 1979) (2013-10-18)
Fiorentina Roviezzo, Antonella De Angelis, Luana De Gruttola, Antonio Bertolino, Nikol Sullo, Vincenzo Brancaleone, Mariarosaria Bucci, Raffaele De Palma, Konrad Urbanek, Bruno D'Agostino, Angela Ianaro, Raffaella Sorrentino, Giuseppe Cirino
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Nω-硝基-L-精氨酸甲酯 盐酸盐, ≥98% (TLC), powder
Sigma-Aldrich
渥曼青霉素, from Penicillium funiculosum, ≥98% (HPLC and TLC)
Sigma-Aldrich
鞘氨醇-1-磷酸, ≥95%, powder
Sigma-Aldrich
鞘氨醇-1-磷酸, ≥98.0% (TLC)
Sigma-Aldrich
Wortmannin,现配溶液, from Penicillium funiculosum, ≥95% (HPLC)
Sigma-Aldrich
D-鞘氨醇, synthetic
Sigma-Aldrich
D-鞘氨醇, ≥98.0% (TLC)
Supelco
甲磺酸加贝酯, analytical standard, for drug analysis