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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.

Author information

1
Department of Pharmacology, University of Illinois at Chicago, Chicago, IL.
2
Hematopoietic Stem Cell Transplantation Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, China.
3
School of Medical Laboratory, Tianjin Medical University, Tianjin, China.
4
Woodruff School of Mechanical Engineering and.
5
Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA.
6
Dupage Medical Technology, Inc., Willowbrook, IL; and.
7
Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA.

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 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.

PMID:
29853537
PMCID:
PMC6073322
[Available on 2019-08-02]
DOI:
10.1182/blood-2017-05-785253

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