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Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice

Nature Medicine volume 5, pages 1199–1202 (1999)Cite this article

Abstract

Platelet activation is characterized by shape change, induction of fibrinogen receptor expression and release of granular contents, leading to aggregation and plug formation1. While this response is essential for hemostasis2, it is also important in the pathogenesis of a broad spectrum of diseases, including myocardial infarction, stroke and unstable angina. Adenosine 5'-diphosphate (ADP) induces platelet aggregation, but the mechanism for this has not been established, and the relative contribution of ADP in hemostasis and the development of arterial thrombosis3 is poorly understood. We show here that the purinoceptor P2Y1 is required for platelet shape change in response to ADP and is also a principal receptor mediating ADP-induced platelet aggregation. Activation of P2Y1 resulted in increased intracellular calcium but no alteration in cyclic adenosine monophosphate (cAMP) levels. P2Y1-deficient platelets partially aggregated at higher ADP concentrations, and the lack of P2Y1 did not alter the ability of ADP to inhibit cAMP, indicating that platelets express at least one additional ADP receptor. In vivo, the lack of P2Y1 expression increased bleeding time and protected from collagen- and ADP-induced thromboembolism. These findings support the hypothesis that the ATP receptor P2Y1 is a principal receptor mediating both physiologic and pathological ADP-induced processes in platelets.

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Figure 1: Targeted disruption of P2y1 locus and aggregation responses of wild-type (WT) and P2y1–/– platelets.
Figure 2: Cellular events in stimulated P2y1–/– and wild-type platelets.
Figure 3: Effect of the lack of P2Y1 on hemostasis and intravascular formation of thrombi.

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Acknowledgements

We thank J. Snouwaert for help in designing the targeting plasmid; E. Hicks for tissue culture; D. Thomas for assistance in platelet preparation; M. Verghese for assistance in the measurement of calcium; and L. Parise and C. Boudignon for discussions and help with manuscript preparation. This work was supported by NIH grants DKHL 51791 and HL 58554 (B.H.K.) and by an American Heart Association grant 9920376U (J.E.F.).

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  1. Department of Medicine, University of North Carolina, CB# 7248, Chapel Hill, Thurston Bowles Bld, Durham, North Carolina, USA

    Jean-Etienne Fabre, MyTrang Nguyen, Anne Latour, Jayne A. Keifer & Beverly H. Koller

  2. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

    Laurent P. Audoly & Thomas M. Coffman

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  1. Jean-Etienne Fabre
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Correspondence to Beverly H. Koller.

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Fabre, JE., Nguyen, M., Latour, A. et al. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice. Nat Med 5, 1199–1202 (1999). https://doi.org/10.1038/13522

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