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This Article Full Text Full Text (PDF) All Versions of this Article: 74/1/88    most recent biolreprod.105.043034v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hemmings, D. G. Articles by Taggart, M. J. Search for Related Content PubMed PubMed Citation Articles by Hemmings, D. G. Articles by Taggart, M. J. Agricola Articles by Hemmings, D. G. Articles by Taggart, M. J.

Sphingosine-1-Phosphate Acts via Rho-Associated Kinase and Nitric Oxide to Regulate Human Placental Vascular Tone¹

Department of Obstetrics and Gynecology, Perinatal Research Centre,³ University of Alberta, Edmonton, Alberta, Canada T6G 2S2 Maternal and Fetal Health Research Centre, Human Development Group⁴ Smooth Muscle Physiology Group, Cardiovascular Research⁵, University of Manchester, Manchester M13 9WL, United Kingdom

ABSTRACT

Sphingosine-1-phosphate (S1P), a bioactive lipid released from activated platelets, has been demonstrated in animal models to regulate vascular tone through receptor-mediated activation of Rho-associated kinase 1 and nitric oxide synthase 3. The role of S1P in regulation of human vascular tone (particularly during pregnancy, with its unique vascular adaptations and localized platelet activation) is unknown. We hypothesized that S1P would constrict small placental arteries through activation of Rho-associated kinases with modulation by nitric oxide. Reverse transcription-polymerase chain reaction of chorionic plate artery preparations detected mRNAs encoding all five receptors for S1P, and S1P induced dose-dependent vasoconstriction of both chorionic plate and stem villous isobarically mounted arteries, which at 10 µmol/L was 32.9% ± 3.86% (mean ± SEM) and 34.6% ± 7.01%, respectively. In stem villous arteries, S1P-induced vasoconstriction was enhanced significantly following inhibition of nitric oxide synthases with N^G-nitro-L-arginine methyl ester (100 µmol/L, 52.6% ± 6.28%, P < 0.05). The S1P-induced vasoconstriction was reversed by Y27632, an inhibitor of Rho-associated kinases (10 µmol/L) in both chorionic plate (to 14.9% ± 4.95%) and stem villous arteries (to 2.71% ± 6.13%). The S1P added to alpha-toxin-permeabilized, isometrically mounted chorionic plate arteries bathed in submaximal Ca²⁺-activating solution induced Ca²⁺-sensitization of constriction, which was 47.7% ± 10.0% of that occurring to maximal Ca²⁺-activating solution. This was reduced by Y27632 to 18.4% ± 18.4%. Interestingly, S1P-induced vasoconstriction occurred in all isobarically mounted arteries but was inconsistent in isometrically mounted chorionic plate arteries. In summary, S1P-induced vasoconstriction in human placental arteries is mediated by increased Ca²⁺-sensitization through activation of Rho-associated kinases, and this vasoconstriction also is modulated by nitric oxide. Identification of these actions of S1P in the placental vasculature is important for understanding both normal and potentially abnormal vascular adaptations with pregnancy.

calcium, kinases, nitric oxide, placenta, pregnancy

¹ Supported by Ardana Bioscience and the Canadian Institutes of Health Research (CIHR). D.G.H. is supported jointly by the Heart and Stroke Foundation of Canada and CIHR. S.T.D. is supported jointly by a Canada Research Chair in Women's Cardiovascular Health and as a Senior Scholar of the Alberta Heritage Foundation for Medical Research.

² Correspondence: Denise G. Hemmings, Department of Obstetrics and Gynecology, Perinatal Research Centre, 232 HMRC, University of Alberta, Edmonton, AB, Canada T6G 2S2. FAX: 780 492 1308; denise.hemmings{at}ualberta.ca

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