Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis
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Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis. / Pleines, Irina; Hagedorn, Ina; Gupta, Shuchi; May, Frauke; Chakarova, Lidija; van Hengel, Jolanda; Offermanns, Stefan; Krohne, Georg; Kleinschnitz, Christoph; Brakebusch, Cord; Nieswandt, Bernhard.
In: Blood, Vol. 119, No. 4, 01.11.2011, p. 1054-63.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis
AU - Pleines, Irina
AU - Hagedorn, Ina
AU - Gupta, Shuchi
AU - May, Frauke
AU - Chakarova, Lidija
AU - van Hengel, Jolanda
AU - Offermanns, Stefan
AU - Krohne, Georg
AU - Kleinschnitz, Christoph
AU - Brakebusch, Cord
AU - Nieswandt, Bernhard
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Vascular injury initiates rapid platelet activation that is critical for hemostasis, but it also may cause thrombotic diseases, such as myocardial infarction or ischemic stroke. Reorganizations of the platelet cytoskeleton are crucial for platelet shape change and secretion and are thought to involve activation of the small GTPase RhoA. In this study, we analyzed the in vitro and in vivo consequences of megakaryocyte- and platelet-specific RhoA gene deletion in mice. We found a pronounced macrothrombocytopenia in RhoA-deficient mice, with platelet counts of approximately half that of wild-type controls. The mutant cells displayed an altered shape but only a moderately reduced life span. Shape change of RhoA-deficient platelets in response to G(13)-coupled agonists was abolished, and it was impaired in response to G(q) stimulation. Similarly, RhoA was required for efficient secretion of a and dense granules downstream of G(13) and G(q). Furthermore, RhoA was essential for integrin-mediated clot retraction but not for actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo, RhoA deficiency resulted in markedly prolonged tail bleeding times but also significant protection in different models of arterial thrombosis and in a model of ischemic stroke. Together, these results establish RhoA as an important regulator of platelet function in thrombosis and hemostasis.
AB - Vascular injury initiates rapid platelet activation that is critical for hemostasis, but it also may cause thrombotic diseases, such as myocardial infarction or ischemic stroke. Reorganizations of the platelet cytoskeleton are crucial for platelet shape change and secretion and are thought to involve activation of the small GTPase RhoA. In this study, we analyzed the in vitro and in vivo consequences of megakaryocyte- and platelet-specific RhoA gene deletion in mice. We found a pronounced macrothrombocytopenia in RhoA-deficient mice, with platelet counts of approximately half that of wild-type controls. The mutant cells displayed an altered shape but only a moderately reduced life span. Shape change of RhoA-deficient platelets in response to G(13)-coupled agonists was abolished, and it was impaired in response to G(q) stimulation. Similarly, RhoA was required for efficient secretion of a and dense granules downstream of G(13) and G(q). Furthermore, RhoA was essential for integrin-mediated clot retraction but not for actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo, RhoA deficiency resulted in markedly prolonged tail bleeding times but also significant protection in different models of arterial thrombosis and in a model of ischemic stroke. Together, these results establish RhoA as an important regulator of platelet function in thrombosis and hemostasis.
KW - Animals
KW - Bleeding Time
KW - Blood Platelets
KW - Brain Infarction
KW - Calcium Signaling
KW - Cell Shape
KW - Cell Size
KW - Clot Retraction
KW - GTP-Binding Protein alpha Subunits, G12-G13
KW - GTP-Binding Protein alpha Subunits, Gq-G11
KW - Hemostasis
KW - Kinetics
KW - Megakaryocytes
KW - Mice
KW - Mice, Knockout
KW - Platelet Activation
KW - Platelet Count
KW - Thrombocytopenia
KW - Thrombosis
KW - rho GTP-Binding Proteins
U2 - 10.1182/blood-2011-08-372193
DO - 10.1182/blood-2011-08-372193
M3 - Journal article
C2 - 22045984
VL - 119
SP - 1054
EP - 1063
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -
ID: 40355685