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Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion.: Role of myosin IIA in hemostasis and thrombosis

Abstract : Mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain IIA result in bleeding disorders characterized by a macrothrombocytopenia. To understand the role of myosin in normal platelet functions and in pathology, we generated mice with disruption of MYH9 in megakaryocytes. MYH9Delta mice displayed macrothrombocytopenia with a strong increase in bleeding time and absence of clot retraction. However, platelet aggregation and secretion in response to any agonist were near normal despite absence of initial platelet contraction. By contrast, integrin outside-in signaling was impaired, as observed by a decrease in integrin beta3 phosphorylation and PtdIns(3,4)P(2) accumulation following stimulation. Upon adhesion on a fibrinogen-coated surface, MYH9Delta platelets were still able to extend lamellipodia but without stress fiber-like formation. As a consequence, thrombus growth and organization, investigated under flow by perfusing whole blood over collagen, were strongly impaired. Thrombus stability was also decreased in vivo in a model of FeCl(3)-induced injury of carotid arteries. Overall, these results demonstrate that while myosin seems dispensable for aggregation and secretion in suspension, it plays a key role in platelet contractile phenomena and outside-in signaling. These roles of myosin in platelet functions, in addition to thrombocytopenia, account for the strong hemostatic defects observed in MYH9Delta mice.
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https://www.hal.inserm.fr/inserm-00166437
Contributor : Catherine Léon <>
Submitted on : Thursday, July 24, 2008 - 4:56:37 PM
Last modification on : Thursday, April 23, 2020 - 2:26:29 PM
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Catherine Léon, Anita Eckly, Béatrice Hechler, Boris Aleil, Monique Freund, et al.. Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion.: Role of myosin IIA in hemostasis and thrombosis. Blood, American Society of Hematology, 2007, 110 (9), pp.3183-91. ⟨10.1182/blood-2007-03-080184⟩. ⟨inserm-00166437⟩

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