title: Modulation of human arterial tone during pregnancy: the effect of the bioactive metabolite sphingosine-1-phosphate.
abstract: Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that has been implicated in cardiovascular disease. The objective of the present study was to determine the vasoactive effects and underlying mechanisms of S1P on adult human maternal arteries. The isometric tensions of the omental and myometrial arteries isolated from normal pregnant women at term were assessed in response to incremental doses of S1P in the presence or absence of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact arteries and in those permeabilized with alpha-toxin, to study agonist-dependent calcium-sensitization, was assessed with the inhibitor Y27632. Real-time RT-PCR established the presence of mRNA encoding the S1P receptors (S1P(1) to (3)), previously known as endothelial differentiation gene receptors (EDG1, 3 and 5), in both artery types. S1P induced a dose-dependent increase in the isometric tension of all the arteries. Y27632 reduced constriction due to S1P in intact arteries and reduced S1P-induced sensitization of contraction to submaximal activating Ca(2+) in permeabilized arteries. L-NAME also modulated S1P vasoactive responses in a tissue-specific manner. Two subgroups of omental arteries were identified, one of which utilizes the NO pathway. In myometrial arteries, S1P evoked oscillatory constrictions, whereas pretreatment with L-NAME resulted in only tonic constrictions of unaltered peak magnitude. The prominent vasoactive actions of S1P in the maternal arteries of pregnant women are modulated by inhibitors of ROCKs and NO bioavailability. The subtle tissue-specific functional differences in the modulation of S1P actions by NO have important implications for vascular tone regulation by this bioactive circulatory metabolite during pregnancy.
authors.affiliation: Maternal and Fetal Health Research Centre, Division of Human Development, University of Manchester, Manchester M13 0JH, United Kingdom. nicola.hudson@manchester.ac.uk
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Hudson
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Hara
authors.forename: Helen A
authors.initials: HA
authors.lastname: Lacey
authors.forename: Jemma
authors.initials: J
authors.lastname: Corcoran
authors.forename: Denise G
authors.initials: DG
authors.lastname: Hemmings
authors.forename: Mark
authors.initials: M
authors.lastname: Wareing
authors.forename: Philip
authors.initials: P
authors.lastname: Baker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Taggart
mesh_terms: D001158:Arteries / Q000187:drug effects* / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D009215:Myometrium / Q000098:blood supply* / Q000378:metabolism; D009852:Omentum / Q000098:blood supply / Q000378:metabolism; D011247:Pregnancy; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D046509:Tissue Culture Techniques; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D016326:Extracellular Matrix Proteins; D008246:Lysophospholipids; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine