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Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis

Irina Pleines, Ina Hagedorn, Shuchi Gupta, Frauke May, Lidija Chakarova, Jolanda van Hengel UGent, Stefan Offermanns, Georg Krohne, Christoph Kleinschnitz and Cord Brakebusch, et al. (2012) BLOOD. 119(4). p.1054-1063
abstract
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
MOLECULAR-MECHANISMS, SIGNALING PATHWAYS, IN-VIVO, INTEGRIN ALPHA(IIB)BETA(3), SHAPE CHANGE, ISCHEMIC-STROKE, KINASE, PROTEIN, MYOSIN, MICE
journal title
BLOOD
Blood
volume
119
issue
4
pages
1054 - 1063
Web of Science type
Article
Web of Science id
000299860700021
JCR category
HEMATOLOGY
JCR impact factor
9.06 (2012)
JCR rank
3/66 (2012)
JCR quartile
1 (2012)
ISSN
0006-4971
DOI
10.1182/blood-2011-08-372193
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2976280
handle
http://hdl.handle.net/1854/LU-2976280
date created
2012-08-29 12:36:08
date last changed
2012-09-06 10:16:42
@article{2976280,
  abstract     = {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.},
  author       = {Pleines, Irina and Hagedorn, Ina and Gupta, Shuchi and May, Frauke and Chakarova, Lidija and van Hengel, Jolanda and Offermanns, Stefan and Krohne, Georg and Kleinschnitz, Christoph and Brakebusch, Cord and Nieswandt, Bernhard},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {MOLECULAR-MECHANISMS,SIGNALING PATHWAYS,IN-VIVO,INTEGRIN ALPHA(IIB)BETA(3),SHAPE CHANGE,ISCHEMIC-STROKE,KINASE,PROTEIN,MYOSIN,MICE},
  language     = {eng},
  number       = {4},
  pages        = {1054--1063},
  title        = {Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis},
  url          = {http://dx.doi.org/10.1182/blood-2011-08-372193},
  volume       = {119},
  year         = {2012},
}

Chicago
Pleines, Irina, Ina Hagedorn, Shuchi Gupta, Frauke May, Lidija Chakarova, Jolanda van Hengel, Stefan Offermanns, et al. 2012. “Megakaryocyte-specific RhoA Deficiency Causes Macrothrombocytopenia and Defective Platelet Activation in Hemostasis and Thrombosis.” Blood 119 (4): 1054–1063.
APA
Pleines, I., Hagedorn, I., Gupta, S., May, F., Chakarova, L., van Hengel, J., Offermanns, S., et al. (2012). Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis. BLOOD, 119(4), 1054–1063.
Vancouver
1.
Pleines I, Hagedorn I, Gupta S, May F, Chakarova L, van Hengel J, et al. Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis. BLOOD. 2012;119(4):1054–63.
MLA
Pleines, Irina, Ina Hagedorn, Shuchi Gupta, et al. “Megakaryocyte-specific RhoA Deficiency Causes Macrothrombocytopenia and Defective Platelet Activation in Hemostasis and Thrombosis.” BLOOD 119.4 (2012): 1054–1063. Print.