alpha 2 beta 1 Integrin, GPVI Receptor, and Common FcR gamma Chain on Mouse Platelets Mediate Distinct Responses to Collagen in Models of Thrombosis

作者：Marjoram Robin J; Li Zhengzhi; He Li; Tollefsen Douglas M; Kunicki Thomas J; Dickeson S Kent; Santoro Samuel A; Zutter Mary M^*

来源：PLos One, 2014, 9(11): e114035.

DOI：10.1371/journal.pone.0114035

Objective: Platelets express the alpha 2 beta 1 integrin and the glycoprotein VI (GPVI)/FcR gamma complex, both collagen receptors. Understanding platelet-collagen receptor function has been enhanced through use of genetically modified mouse models. Previous studies of GPVI/FcR gamma-mediated collagen-induced platelet activation were perfomed with mice in which the FcR gamma subunit was genetically deleted ( FcR gamma(-/-)) or the complex was depleted. The development of alpha 2 beta 1(-/-) and GPVI(-/-) mice permits side-by-side comparison to address contributions of these collagen receptors in vivo and in vitro.
Approach and Results: To understand the different roles played by the a2b1 integrin, the GPVI receptor or FcR gamma subunit in collagen-stimulated hemostasis and thrombosis, we compared alpha 2 beta 1(-/-), FcR gamma(-/-), 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 alpha 2 beta 1 integrin and the GPVI receptor, but not the FcR gamma subunit influence carotid artery occlusion in vivo. In contrast, the GPVI receptor and the FcR gamma chain, but not the alpha 2 beta 1 integrin, play similar roles in intravascular thrombosis in response to soluble Type I collagen. FcR gamma(-/-) platelets showed less attenuation of tyrosine phosphorylation of several proteins including RhoGDI when compared to GPVI(-/-) and wild type platelets. The difference between FcR gamma(-/-) and GPVI(-/-) platelet phosphotyrosine levels correlated with the in vivo thrombosis findings.
Conclusion: Our data demonstrate that genetic deletion of GPVI receptor, FcR gamma chain, or the alpha 2 beta 1 integrin changes the thrombotic potentials of these platelets to collagen dependent on the stimulus mechanism. The data suggest that the FcR gamma 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.

• 出版日期2014-11-21