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

ABSTRACT: 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 ?3-/- platelets or by integrin antagonists. The impaired MV release and PS exposure in ?3-/- platelets were rescued by expression of wild-type ?3 but not a G?13 binding-deficient ?3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of G?13 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 G?13-integrin interaction, suggesting that G?13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of G?13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of G?13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, ?3 integrins serve as a shear sensor activating the G?13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of G?13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.

SUBMITTER: Pang A 

PROVIDER: S-EPMC6073322 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature