A Humanized Glycoprotein VI (GPVI) Mouse Model to Assess the Antithrombotic Efficacies of Anti-GPVI Agents
- 11 January 2012
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 341 (1), 156-163
- https://doi.org/10.1124/jpet.111.189050
Abstract
Glycoprotein VI (GPVI) has been proposed as a promising antiplatelet target, because its blockade prevents experimental thrombosis without impairing hemostasis. The objective of this study was to develop a preclinical tool to evaluate the role of human GPVI (hGPVI) in various models of thrombosis and to screen anti-GPVI compounds. A genetically modified mouse strain expressing hGPVI has been developed using a knockin strategy. The mice were viable and fertile and did not present any hematological defects. Approximately 3700 copies of human GPVI were detected at the platelet surface. Platelet aggregation, fibrinogen binding, and P-selectin exposure were normal in response to various agonists. The 9O12.2 Fab fragment directed against human GPVI bound to hGPVI platelets in vitro and ex vivo and markedly reduced collagen-and collagen-related peptide-induced responses. Injection of 9O12.2 into hGPVI animals did not prolong the tail bleeding time but provided protection against lethal thromboembolism induced by a collagen/adrenaline mixture. In addition, 9O12.2 reduced arterial thrombus growth by 44% after superficial laser injury, 43% after deep laser injury in mice pretreated with hirudin, and 48% after mechanical injury. In conclusion, we have developed a humanized mouse model that could be used in preclinical studies to evaluate the effects of anti-GPVI compounds.Keywords
This publication has 25 references indexed in Scilit:
- Genetic and antibody‐induced glycoprotein VI deficiency equally protects mice from mechanically and FeCl3‐induced thrombosisJournal of Thrombosis and Haemostasis, 2011
- Comparison of two murine models of thrombosis induced by atherosclerotic plaque injuryThrombosis and Haemostasis, 2011
- Diagnostic and Therapeutic Potentials of Platelet Glycoprotein VISeminars in Thrombosis and Hemostasis, 2010
- Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterizationJournal of Thrombosis and Haemostasis, 2009
- Absence of collagen-induced platelet activation caused by compound heterozygous GPVI mutationsBlood, 2009
- Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital modelJournal of Thrombosis and Haemostasis, 2009
- Contribution of platelet glycoprotein VI to the thrombogenic effect of collagens in fibrous atherosclerotic lesionsAtherosclerosis, 2005
- GPVI levels in platelets: relationship to platelet function at high shearBlood, 2003
- Antiplatelet therapy: in search of the 'magic bullet'Nature Reviews Drug Discovery, 2003
- Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamilyBlood, 2000