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Publication Detail
Tuning the endothelial response: differential release of exocytic cargos from Weibel-Palade Bodies.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Nightingale TD, McCormack JJ, Grimes W, Robinson C, Lopes da Silva M, White IJ, Vaughan A, Cramer LP, Cutler DF
  • Publication date:
    09/2018
  • Journal:
    Journal of thrombosis and haemostasis : JTH
  • Medium:
    Print-Electronic
  • Status:
    Published
  • Print ISSN:
    1538-7933
  • Language:
    eng
  • Addresses:
    Centre for Microvascular Research, William Harvey Research Institute, Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M6BQ, UK.
Abstract
Endothelial cells harbour specialised storage organelles, Weibel-Palade Bodies (WPBs). Exocytosis of WPB content into the vascular lumen initiates primary haemostasis, mediated by Von Willebrands factor (VWF) and inflammation, mediated by several proteins including P-selectin. During full fusion, secretion of this large haemostatic protein and smaller pro-inflammatory proteins are thought to be inextricably linked.To determine if secretagogue-dependent differential release of WPB cargo occurs, and whether this is mediated by the formation of an actomyosin ring during exocytosis.We used VWF string analysis, leukocyte rolling assays, ELISA, spinning disk confocal microscopy, high-throughput confocal microscopy and inhibitor and siRNA treatments to demonstrate the existence of cellular machinery that allows differential release of WPB cargo proteins.Inhibition of the actomyosin ring differentially effects two processes regulated by WPB exocytosis; it perturbs VWF string formation but has no effect on leukocyte rolling. The efficiency of ring recruitment correlates with VWF release; the ratio of release of VWF to small cargoes decreases when ring recruitment is inhibited. The recruitment of the actin ring is time-dependent; fusion events occurring directly after stimulation are less likely to initiate haemostasis than later events, and is activated by PKC isoforms.Secretagogues differentially recruit the actomyosin ring, thus demonstrating one mechanism by which the pro-thrombotic effect of endothelial activation can be modulated. This potentially limits thrombosis whilst permitting a normal inflammatory response. These results have implications for the assessment of WPB fusion, cargo-content release and the treatment of patients with von Willebrand disease. This article is protected by copyright. All rights reserved.
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