β1 integrin-mediated signals are required for platelet granule secretion and hemostasis in mouse

Blood. 2013 Oct 10;122(15):2723-31. doi: 10.1182/blood-2013-06-508721. Epub 2013 Sep 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Blood Platelets / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Hemostasis / physiology*
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuropeptides / metabolism
  • Platelet Adhesiveness / physiology
  • Protein Binding / physiology
  • Secretory Vesicles / metabolism*
  • Signal Transduction / physiology*
  • Thrombosis / metabolism
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Actins
  • Cytoskeletal Proteins
  • Integrin beta1
  • Neuropeptides
  • Rac1 protein, mouse
  • kindlin-3 protein, mouse
  • rac1 GTP-Binding Protein