Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
Anne Angelillo-Scherrer, … , Bernhard Wehrle-Haller, Peter Carmeliet
Anne Angelillo-Scherrer, … , Bernhard Wehrle-Haller, Peter Carmeliet
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):237-246. https://doi.org/10.1172/JCI22079.
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Article Hematology

Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

Abstract

Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing “outside-in” signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the β3 integrin, thereby amplifying outside-in signaling via αIIbβ3. Blocking the Gas6-R–αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis.

Authors

Anne Angelillo-Scherrer, Laurent Burnier, Nathalie Flores, Pierre Savi, Maria DeMol, Paul Schaeffer, Jean-Marc Herbert, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Christian Vesin, Marc F. Hoylaerts, Stéphane Plaisance, Désiré Collen, Edward M. Conway, Bernhard Wehrle-Haller, Peter Carmeliet

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Loss of Tyro3, Axl, or Mer protects mice against thrombosis. (A) Stasis-...
Loss of Tyro3, Axl, or Mer protects mice against thrombosis. (A) Stasis-induced thrombosis in the inferior vena cava (mean ± SEM, n = 10). *P < 0.005. (B) Thromboembolism induced by collagen/epinephrine injection in WT (n = 15) and in Tyro3–/– (n = 15), Axl–/– (n = 10), and Mer–/– (n = 12) mice. *P < 0.005. (C and D) Light microscopy (H&E staining) of the lungs after collagen/epinephrine injection, revealing extensive platelet thromboemboli (arrows) in WT mice (C) but not in surviving Axl–/– mice (D) or Tyro3–/– or Mer–/– mice (not shown). Scale bars: 100 μm.