TY - JOUR
T1 - Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation
AU - Pang, Aiming
AU - Cui, Yujie
AU - Chen, Yunfeng
AU - Cheng, Ni
AU - Delaney, M. Keegan
AU - Gu, Minyi
AU - Stojanovic-Terpo, Aleksandra
AU - Zhu, Cheng
AU - Du, Xiaoping
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology
PY - 2018/8/2
Y1 - 2018/8/2
N2 - 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 b32/2 platelets or by integrin antagonists. The impaired MV release and PS exposure in b32/2 platelets were rescued by expression of wild-type b3 but not a Ga13 binding–deficient b3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Ga13 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 Ga13-integrin interaction, suggesting that Ga13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Ga13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Ga13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, b3 integrins serve as a shear sensor activating the Ga13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Ga13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.
AB - 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 b32/2 platelets or by integrin antagonists. The impaired MV release and PS exposure in b32/2 platelets were rescued by expression of wild-type b3 but not a Ga13 binding–deficient b3 mutant (E733EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Ga13 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 Ga13-integrin interaction, suggesting that Ga13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Ga13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Ga13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, b3 integrins serve as a shear sensor activating the Ga13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Ga13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation.
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U2 - 10.1182/blood-2017-05-785253
DO - 10.1182/blood-2017-05-785253
M3 - Article
C2 - 29853537
AN - SCOPUS:85051232193
SN - 0006-4971
VL - 132
SP - 533
EP - 543
JO - Blood
JF - Blood
IS - 5
ER -