Journal
BLOOD
Volume 119, Issue 8, Pages E45-E56Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-09-381400
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Funding
- Funding Program for Next Generation World-Leading Researchers
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science, and Technology, Japan [22113008]
- grants for Translational Systems Biology and Medicine Initiative
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Banyu Life Science Foundation International
- National Institute of Biomedical Innovation
- Grants-in-Aid for Scientific Research [23650214, 22300106, 23591298, 23791016, 21300160, 24659127, 23650622, 24659489, 22113008, 23659533, 22700448, 21390321, 21590230, 23659514, 21591231] Funding Source: KAKEN
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The mechanism by which thrombotic vessel occlusion occurs independently of plaque development or endothelial cell (EC) disruption remains unclear, largely because of an inability to visualize the formation of thrombus, especially at the single-platelet level in real time. Here we demonstrate that rapidly developing thrombi composed of discoid platelets can be induced in the mesenteric capillaries, arterioles, and large-sized arteries of living mice, enabling characterization of the kinetics of thrombosis initiation and the multicellular interrelationships during thrombus development. Platelet aggregation without EC disruption was triggered by reactive oxygen species (ROS) photo-chemically induced by moderate power laser irradiation. The inflammatory cytokines TNF-alpha and IL-1 could be key components of the EC response, acting through regulation of VWF mobilization to the cell surface. Thrombus formation was then initiated by the binding of platelet GPIb alpha to endothelial VWF in our model, and this effect was inhibited by the ROS scavenger N-acetylcysteine. Actin linker talin-dependent activation of alphaIIb-beta3 integrin or Rac1 in platelets was required for late-phase thrombus stability. Our novel imaging technology illustrates the molecular mechanism underlying inflammation-based thrombus formation by discoid platelets on undisrupted ECs and suggests control of ROS could be a useful therapeutic target for the prevention of thrombotic diseases. (Blood. 2012; 119(8): e45-e56)
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