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Sci. Signal., 5 January 2010
Vol. 3, Issue 103, p. ra1
[DOI: 10.1126/scisignal.2000551]

RESEARCH ARTICLES

Impaired {alpha}IIbβ3 Integrin Activation and Shear-Dependent Thrombus Formation in Mice Lacking Phospholipase D1

Margitta Elvers1, David Stegner1, Ina Hagedorn1, Christoph Kleinschnitz2, Attila Braun1, Marijke E. J. Kuijpers3, Michael Boesl4, Qin Chen5, Johan W. M. Heemskerk3, Guido Stoll2, Michael A. Frohman5, and Bernhard Nieswandt1*

1 University Clinic Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
2 Department of Neurology, University Clinic, 97080 Würzburg, Germany.
3 Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, 6200 MD Maastricht, the Netherlands.
4 Max-Planck-Institute for Biochemistry, 82152 Martinsried, Germany.
5 Department of Pharmacology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794–5140, USA.

Abstract: Platelet aggregation is essential for hemostasis but can also cause myocardial infarction and stroke. A key but poorly understood step in platelet activation is the shift of the principal adhesive receptor, {alpha}IIbβ3 integrin, from a low- to high-affinity state for its ligands, a process that enables adhesion and aggregation. In response to stimulation of heterotrimeric guanosine triphosphate–binding protein or immunoreceptor tyrosine-based activation motif–coupled receptors, phospholipases cleave membrane phospholipids to generate lipid and soluble second messengers. An essential role in platelet activation has been established for phospholipase C (PLC) but not for PLD and its product phosphatidic acid. Here, we report that platelets from Pld1–/– mice displayed impaired {alpha}IIbβ3 integrin activation in response to major agonists and defective glycoprotein Ib–dependent aggregate formation under high shear conditions. These defects resulted in protection from thrombosis and ischemic brain infarction without affecting tail bleeding times. These results indicate that PLD1 may be a critical regulator of platelet activity in the setting of ischemic cardiovascular and cerebrovascular events.

* To whom correspondence should be addressed. E-mail: bernhard.nieswandt{at}virchow.uni-wuerzburg.de

Citation: M. Elvers, D. Stegner, I. Hagedorn, C. Kleinschnitz, A. Braun, M. E. J. Kuijpers, M. Boesl, Q. Chen, J. W. M. Heemskerk, G. Stoll, M. A. Frohman, B. Nieswandt, Impaired {alpha}IIbβ3 Integrin Activation and Shear-Dependent Thrombus Formation in Mice Lacking Phospholipase D1. Sci. Signal. 3, ra1 (2010).

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