title: Megakaryocyte-specific RhoA deficiency causes macrothrombocytopenia and defective platelet activation in hemostasis and thrombosis.
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 α 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.
authors: Chair of Vascular Medicine, University Hospital Würzburg and Rudolf Virchow Center, DFG-Research Center for Experimental Biomedicine, Josef-Schneider-Strasse 2,Würzburg, Germany.
authors: Irina
authors: I
authors: Pleines
authors: Ina
authors: I
authors: Hagedorn
authors: Shuchi
authors: S
authors: Gupta
authors: Frauke
authors: F
authors: May
authors: Lidija
authors: L
authors: Chakarova
authors: Jolanda
authors: J
authors: van Hengel
authors: Stefan
authors: S
authors: Offermanns
authors: Georg
authors: G
authors: Krohne
authors: Christoph
authors: C
authors: Kleinschnitz
authors: Cord
authors: C
authors: Brakebusch
authors: Bernhard
authors: B
authors: Nieswandt
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000473:pathology*; D020520:Brain Infarction / Q000517:prevention & control; D020013:Calcium Signaling; D048430:Cell Shape; D048429:Cell Size; D003018:Clot Retraction; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000737:chemistry; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry; D006487:Hemostasis / Q000187:drug effects; D007700:Kinetics; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects; D010976:Platelet Count; D013921:Thrombocytopenia / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013927:Thrombosis / Q000517:prevention & control*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein