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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 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 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 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. Related Collections Cell Adhesion and Motility Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 May 2003, Vol. 101, No. 10, pp. 3969-3976 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype Cécile 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 From the Center for Molecular and Vascular Biology and the Laboratory of Morphology and Molecular Pathology, University of Leuven, Belgium; and the Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands. 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 adenosine diphosphate (ADP) or thrombin were normal. Perfusing whole blood from transgenic mice over collagen fibers at a shear rate of 1000 seconds1 resulted in increased P2X1-dependent aggregate formation and phosphatidylserine exposure. Platelet hyperreactivity to collagen was correlated with up-regulated extracellular signal-regulated kinase 2 (ERK2) phosphorylation. Accordingly, the MEK1/2 inhibitor U0126 potently inhibited the collagen-induced aggregation of transgenic platelets when stirred or when perfused over a collagen surface. In a viscometer, shear stress caused potent aggregation of transgenic platelets under conditions in which 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, it 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. 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