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

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

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Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
Hematopoietic Stem Cell Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, China.
School of Medical Laboratory, Tianjin Medical University, Tianjin, China.
Woodruff School of Mechanical Engineering and.
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA.
Dupage Medical Technology, Inc., Willowbrook, IL; and.
Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA.


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.

[Available on 2019-08-02]

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