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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-10-3215. This Article Full Text (PDF) All Versions of this Article: 2002-10-3215v1 101/10/3969    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Oury, C. Articles by Hoylaerts, M. F Search for Related Content PubMed PubMed Citation Articles by Oury, C. Articles by Hoylaerts, M. F Social Bookmarking                   What's this? Submitted October 24, 2002 Accepted January 4, 2003 Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype Cecile Oury, Marijke J E Kuijpers, Emese Toth-Zsamboki, Arnaud Bonnefoy, Sophie Danloy, Ingrid Vreys, Marion A H Feijge, Rita De Vos, Jos Vermylen, Johan W M Heemskerk, and Marc F Hoylaerts* Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium Laboratory of Morphology and Pathology, University of Leuven, Leuven, Belgium Department of Biochemistry, CARIM, University of Maastricht, Maastricht, The Netherlands * Corresponding author; email: marc.hoylaerts{at}med.kuleuven.ac.be. We have generated transgenic mice overexpressing the human P2X1 ion channel in the megakaryocytic cell lineage. Platelets from transgenic mice exhibited a gain of P2X1 ionotropic activity as determined by more prominent P2X1-mediated Ca2+ influx and platelet shape change. P2X1 overexpression enhanced platelet secretion and aggregation evoked by low doses of collagen, convulxin or the thromboxane A2 mimetic U46619. In contrast, transgenic platelet responses to ADP or thrombin were normal. Perfusing whole blood from transgenic mice over collagen fibers at a shear rate of 1000 s-1 resulted in increased P2X1-dependent aggregate formation and phosphatidylserine exposure. Platelet hyperreactivity to collagen was corrolated with upregulated extracellular signal-regulated kinase 2 (ERK2) phosphorylation. Accordingly, the MEK1/2 inhibitor U0126 potently inhibited collagen-induced transgenic platelet aggregation both under stirring and over a collagen surface under flow. In a viscometer, shear stress caused potent aggregation of transgenic platelets in conditions where wild-type platelets did not aggregate.In an in vivo model of thromboembolism consisting of intravenous injection of a low dose of collagen plus epinephrine, transgenic mice died more readily than wild-type mice. Preinjection of U0126 not only fully protected transgenic mice against thrombosis, but also enhanced the survival of wild-type mice injected with a higher collagen dose. Hence, the platelet P2X1 ion channel plays a role in hemostasis and thrombosis through its participation in collagen-, thromboxane A2 and shear stress-triggered platelet responses. Activation of the ERK2 pathway is instrumental in these processes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Mazzucato, M. R. Cozzi, M. Battiston, M. Jandrot-Perrus, M. Mongiat, P. Marchese, T. J. Kunicki, Z. M. Ruggeri, and L. 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