title: α2β1 integrin, GPVI receptor, and common FcRγ chain on mouse platelets mediate distinct responses to collagen in models of thrombosis.
abstract: OBJECTIVE
  Platelets express the α2β1 integrin and the glycoprotein VI (GPVI)/FcRγ complex, both collagen receptors. Understanding platelet-collagen receptor function has been enhanced through use of genetically modified mouse models. Previous studies of GPVI/FcRγ-mediated collagen-induced platelet activation were perfomed with mice in which the FcRγ subunit was genetically deleted (FcRγ-/-) or the complex was depleted. The development of α2β1-/- and GPVI-/- mice permits side-by-side comparison to address contributions of these collagen receptors in vivo and in vitro.
  
  
  RESULTS
  To understand the different roles played by the α2β1 integrin, the GPVI receptor or FcRγ subunit in collagen-stimulated hemostasis and thrombosis, we compared α2β1-/-, FcRγ-/-, and GPVI-/- mice in models of endothelial injury and intravascular thrombosis in vivo and their platelets in collagen-stimulated activation in vitro. We demonstrate that both the α2β1 integrin and the GPVI receptor, but not the FcRγ subunit influence carotid artery occlusion in vivo. In contrast, the GPVI receptor and the FcRγ chain, but not the α2β1 integrin, play similar roles in intravascular thrombosis in response to soluble Type I collagen. FcRγ-/- platelets showed less attenuation of tyrosine phosphorylation of several proteins including RhoGDI when compared to GPVI-/- and wild type platelets. The difference between FcRγ-/- and GPVI-/- platelet phosphotyrosine levels correlated with the in vivo thrombosis findings.
  
  
  CONCLUSIONS
  Our data demonstrate that genetic deletion of GPVI receptor, FcRγ chain, or the α2β1 integrin changes the thrombotic potentials of these platelets to collagen dependent on the stimulus mechanism. The data suggest that the FcRγ chain may provide a dominant negative effect through modulating signaling pathways in platelets involving several tyrosine phosphorylated proteins such as RhoGDI. In addition, these findings suggest a more complex signaling network downstream of the platelet collagen receptors than previously appreciated.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Marjoram
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: Zhengzhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States of America.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Tollefsen
authors.affiliation: Children's Hospital of Orange County, Orange, CA, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kunicki
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: S Kent
authors.initials: SK
authors.lastname: Dickeson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Santoro
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Zutter
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D003094:Collagen / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D038982:Integrin alpha2beta1; D010980:Platelet Membrane Glycoproteins; D017452:Receptors, IgG; C098341:platelet membrane glycoprotein VI; D003094:Collagen