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Rôle du facteur d’échange nucléotidique Arhgef1 dans l’hémostase

Abstract : One of the major properties of thrombin is the pleiotropic character of its physiological and pathological effects in both the blood and the tissue compartment of the vessel wall. The RhoA signaling pathway is activated by the binding of thrombin to the PARs receptors and this pathway is a major regulator of mechanotransduction and cellular plasticity. The RhoA exchange factor, Arhgef1, is involved in the development of angiotensin II-dependent hypertension and in atherothrombosis. Our hypothesis is that the control of intracellular RhoA signaling by Arhgef1 is a regulatory element of plasma coagulation and could participate in phenotypic modifications of platelets and vascular cells and thus contribute to the increase of tissue thrombin generation. The objectives were to characterize thrombin generation and platelet function from their activation to their implications in a model of tissue thrombosis, and to study the prothrombotic role of vascular smooth muscle cells (VSMCs) in Arhgef1 -/- mice. Results: Arhgef1 -/- mice had a normal platelet count but showed a significant decrease in platelet activation, thrombin generation in whole blood and in the presence of platelets (but not in platelet poor plasma) and platelet adhesion compared to control mice. These modifications result, in vivo, by a greater number of transitory stopping of the blood flow in the tail bleeding model and an increase in the time of occurrence of the carotid occlusive thrombus in response to FeCl3 in Arhgef1 -/- mice compared to controls. The VSMCs of Arhgef1 -/- mice generate less thrombin at their surface and have decreased proliferation compared to VSMCs of the control mice. In conclusion, the results demonstrate the role of Arhgef1 in platelet function and in the regulating of the phenotype of VSMCs. The main mechanism involves Rho GTPase in platelet adhesion and in thrombin generation at the VSMC surface that control thrombus formation. These results suggest that this exchange factor is able to amplify aterial thrombosis and could be involved via thrombin receptors in tissue thrombin-cell stiffness coupling via platelets and VSMCs in vascular pathologies.
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Submitted on : Thursday, October 1, 2020 - 9:20:17 AM
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Camille Rouillon. Rôle du facteur d’échange nucléotidique Arhgef1 dans l’hémostase. Biochimie, Biologie Moléculaire. Université de Lorraine, 2019. Français. ⟨NNT : 2019LORR0092⟩. ⟨tel-02393599⟩



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