Differential Role of Glycoprotein VI in Mouse and Human Thrombus Progression and Stability

Janus-Bell, Emily; Ahmed, Muhammad Usman; Receveur, Nicolas; Mouriaux, Clarisse; Nieswandt, Bernhard; Gardiner, Elizabeth E.; Gachet, Christian; Jandrot‐Perrus, Martine; Mangin, P

doi:10.1055/s-0040-1718737

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…These data are in agreement with our flow cytometry results, showing no binding to GPVI on the platelet surface in these animals. The previous studies revealed discrepancies between the mouse and human GPVI affinity to specific ligands and discussed possible differences with regard to the relevance of this receptor in thrombosis [ 41 ], thus, underscoring the need to utilize humanized animal models. Indeed, our newly generated mouse line allowed us to faithfully reproduce the results obtained with human platelets, thereby excluding the possible overlapping effects of FcγRIIa, which is present in human but not mouse platelets and signals through a similar pathway as GPVI.…”

Section: Discussionmentioning

confidence: 99%

Targeting of a Conserved Epitope in Mouse and Human GPVI Differently Affects Receptor Function

Navarro

Starke

Heemskerk

et al. 2022

IJMS

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Glycoprotein (GP) VI is the major platelet collagen receptor and a promising anti-thrombotic target. This was first demonstrated in mice using the rat monoclonal antibody JAQ1, which completely blocks the Collagen-Related Peptide (CRP)-binding site on mouse GPVI and efficiently inhibits mouse platelet adhesion, activation and aggregation on collagen. Here, we show for the first time that JAQ1 cross-reacts with human GPVI (huGPVI), but not with GPVI in other tested species, including rat, rabbit, guinea pig, swine, and dog. We further demonstrate that JAQ1 differently modulates mouse and human GPVI function. Similar to its effects on mouse GPVI (mGPVI), JAQ1 inhibits CRP-induced activation in human platelets, whereas, in stark contrast to mouse GPVI, it does not inhibit the adhesion, activation or aggregate formation of human platelets on collagen, but causes instead an increased response. This effect was also seen with platelets from newly generated human GPVI knockin mice (hGP6tg/tg). These results indicate that the binding of JAQ1 to a structurally conserved epitope in GPVI differently affects its function in human and mouse platelets.

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Section: Discussionmentioning

confidence: 99%

Targeting of a Conserved Epitope in Mouse and Human GPVI Differently Affects Receptor Function

Navarro

Starke

Heemskerk

et al. 2022

IJMS

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“…This finding indicates that GPVI mediates a signal following platelet adhesion to fibrinogen which is distinct from αIIb|33 outside-in signaling and that the signaling measured upon platelet adhesion to fibrinogen cannot be exclusively related to outside-in signaling as reported so far. Importantly, only human but not murine GPVI is a functional receptor for fibrinogen, 78 which explains a long unanswered question why resting mouse platelets deposited on immobilized fibrinogen do not spread. This was notably demonstrated by the observation that expression of human GPVI in mouse platelets led to a nice spreading on fibrinogen as human platelets do.…”

Section: The Activation State Of Integrins and Integrin Signalingmentioning

confidence: 99%

The relative importance of platelet integrins in hemostasis, thrombosis and beyond

Janus-Bell

Mangin

2023

haematol

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Integrins are heterodimeric transmembrane receptors composed of α and β chains, with an N-terminal extracellular domain forming a globular head corresponding to the ligand binding site. Integrins regulate various cellular functions including adhesion, migration, proliferation, spreading and apoptosis. On platelets, integrins play a central role in adhesion and aggregation on subendothelial matrix proteins of the vascular wall, thereby ensuring hemostasis. Platelet integrins belong either to the β1 family (α2β1, α5β1 and α6β1) or to the β3 family (αIIbβ3 and αvβ3). On resting platelets, integrins can engage their ligands when the latter are immobilized but not in their soluble form. The effects of various agonists promote an inside-out signal in platelets, increasing the affinity of integrins for their ligands and conveying a modest signal reinforcing platelet activation, called outside-in signaling. This outside-in signal ensures platelet adhesion, shape change, granule secretion and aggregation. In this review, we examine the role of each platelet integrin in hemostatic plug formation, hemostasis and arterial thrombosis and also beyond these classical functions, notably in tumor metastasis and sepsis.

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“…A comparison of the roles of human and mouse GPVI in platelet aggregation and thrombus stability indicated that especially the blockage of human platelet GPVI led to disaggregation [ 42 ]. In mice, most markedly a deficiency in integrin β3 led to a transient collagen-mediated platelet aggregation and an unstable thrombus formation [ 43 ].…”

Section: Collagen Gpvi Receptor Stimulationmentioning

confidence: 99%

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

Zou

Swieringa

Laat

et al. 2022

IJMS

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Integrin αIIbβ3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The αIIbβ3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet αIIbβ3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin αIIbβ3. Our analysis points to the (autocrine) ADP P2Y1 and P2Y12 receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.

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Differential Role of Glycoprotein VI in Mouse and Human Thrombus Progression and Stability

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Cited by 6 publications

References 9 publications

Targeting of a Conserved Epitope in Mouse and Human GPVI Differently Affects Receptor Function

Targeting of a Conserved Epitope in Mouse and Human GPVI Differently Affects Receptor Function

The relative importance of platelet integrins in hemostasis, thrombosis and beyond

Reversible Platelet Integrin αIIbβ3 Activation and Thrombus Instability

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