Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation

Blood. 2018 Aug 2;132(5):533-543. doi: 10.1182/blood-2017-05-785253. Epub 2018 May 31.


It is currently unclear why agonist-stimulated platelets require shear force to efficiently externalize the procoagulant phospholipid phosphatidylserine (PS) and release PS-exposed microvesicles (MVs). We reveal that integrin outside-in signaling is an important mechanism for this requirement. PS exposure and MV release were inhibited in β3-/- platelets or by integrin antagonists. The impaired MV release and PS exposure in β3-/- platelets were rescued by expression of wild-type β3 but not a Gα13 binding-deficient β3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Gα13 or Src also diminished agonist/shear-dependent PS exposure and MV release, further indicating a role for integrin outside-in signaling. PS exposure in activated platelets was induced by application of pulling force via an integrin ligand, which was abolished by inhibiting Gα13-integrin interaction, suggesting that Gα13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Gα13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Gα13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, β3 integrins serve as a shear sensor activating the Gα13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Gα13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Blood Coagulation*
  • Blood Platelets / physiology*
  • Cell-Derived Microparticles / metabolism*
  • GTP-Binding Protein alpha Subunits, G12-G13 / physiology*
  • Integrin beta3 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphatidylserines / metabolism*
  • Shear Strength*
  • Signal Transduction
  • Thrombosis / physiopathology


  • Integrin beta3
  • Phosphatidylserines
  • GTP-Binding Protein alpha Subunits, G12-G13