title: LPA1receptor-mediated thromboxane A2release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction.
abstract: Lysophosphatidic acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA1, LPA2, LPA4, and LPA6In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA1-3agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA1&3antagonist Ki16425, and genetic deletion of LPA1but not that of LPA2or inhibition of LPA3, by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TP KO). VPC31143 increased thromboxane A2(TXA2) release from TA of wild-type, TP-KO, and LPA2-KO mice but not from LPA1-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA1-, Gi-, and COX1-dependent autocrine/paracrine TXA2release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA1and TXA2/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklós, Z., Nüsing, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Benyó, Z. LPA1receptor-mediated thromboxane A2release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction.
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Péter Tibor
authors.initials: PT
authors.lastname: Dancs
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Éva
authors.initials: É
authors.lastname: Ruisanchez
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Balogh
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Cecília Rita
authors.initials: CR
authors.lastname: Panta
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Miklós
authors.affiliation: Institute of Clinical Pharmacology, Goethe University, Frankfurt, Germany.
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA; and.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA; gtigyi@uthsc.edu.
authors.forename: Gábor
authors.initials: G
authors.lastname: Tigyi
authors.affiliation: Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary; benyo.zoltan@med.semmelweis-univ.hu.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Benyó
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism*; D014661:Vasoconstriction
chemical_list: D008246:Lysophospholipids; D008565:Membrane Proteins; D049368:Receptors, Lysophosphatidic Acid; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse
keywords: LPA; TP receptor; endothelial dysfunction; platelet activation; vasoconstriction