| First Author | Pang A | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 5 | Pages | 533-543 |
| PubMed ID | 29853537 | Mgi Jnum | J:266030 |
| Mgi Id | MGI:6201862 | Doi | 10.1182/blood-2017-05-785253 |
| Citation | Pang A, et al. (2018) Shear-induced integrin signaling in platelet phosphatidylserine exposure, microvesicle release, and coagulation. Blood 132(5):533-543 |
| abstractText | 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 beta3(-/-) platelets or by integrin antagonists. The impaired MV release and PS exposure in beta3(-/-) platelets were rescued by expression of wild-type beta3 but not a Galpha13 binding-deficient beta3 mutant (E(733)EE to AAA), which blocks outside-in signaling but not ligand binding. Inhibition of Galpha13 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 Galpha13-integrin interaction, suggesting that Galpha13-dependent transmission of mechanical signals by integrins induces PS exposure. Inhibition of Galpha13 delayed coagulation in vitro. Furthermore, inhibition or platelet-specific knockout of Galpha13 diminished laser-induced intravascular fibrin formation in arterioles in vivo. Thus, beta3 integrins serve as a shear sensor activating the Galpha13-dependent outside-in signaling pathway to facilitate platelet procoagulant function. Pharmacological targeting of Galpha13-integrin interaction prevents occlusive thrombosis in vivo by inhibiting both coagulation and platelet thrombus formation. |
