title: β1 integrin-mediated signals are required for platelet granule secretion and hemostasis in mouse.
abstract: Integrins are critical for platelet adhesion and aggregation during arterial thrombosis and hemostasis. Although the platelet-specific αIIbβ3 integrin is known to be crucial for these processes, the in vivo role of β1 integrins is a matter of debate. Here we demonstrate that mice expressing reduced levels of β1 integrins or an activation-deficient β1 integrin show strongly reduced platelet adhesion to collagen in vitro and in a carotis ligation model in vivo. Interestingly, hypomorphic mice expressing only 3% of β1 integrins on platelets show normal bleeding times despite reduced platelet adhesion. The residual 3% of β1 integrins are able to trigger intracellular signals driving Rac-1-dependent granule release required for platelet aggregation and hemostasis. Our findings support a model, in which platelet β1 integrins serve as an important signaling receptor rather than an adhesion receptor in vivo and therefore promote β1 integrins as a promising and so far clinically unemployed antithrombotic target.
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Petzold
authors.forename: Raphael
authors.initials: R
authors.lastname: Ruppert
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Pandey
authors.forename: Verena
authors.initials: V
authors.lastname: Barocke
authors.forename: Hannelore
authors.initials: H
authors.lastname: Meyer
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Siess
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D006487:Hemostasis / Q000502:physiology*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013927:Thrombosis / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D019012:Integrin beta1; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C527818:kindlin-3 protein, mouse; D020830:rac1 GTP-Binding Protein