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Tuning the endothelial response: differential release of exocytic cargos from Weibel‐Palade bodies
Author(s): ,
T. D. Nightingale
Affiliations:
Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
,
J. J. McCormack
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK
,
W. Grimes
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK. Imaging Informatics Division, Bioinformatics Institute, Singapore
,
C. Robinson
Affiliations:
Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
,
M. Lopes da Silva
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK
,
I. J. White
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK
,
A. Vaughan
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK
,
L. P. Cramer
Affiliations:
MRC Laboratory of Molecular Cell Biology, University College London, London, UK. Department of Cell and Developmental Biology, University College, London, UK
D. F. Cutler
Affiliations:
Centre for Microvascular Research, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Correspondence: Daniel F. Cutler, MRC Laboratory for Molecular Cell Biology, Cell Biology Unit and Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E6BT, UK|Tel.: +44 20 7679 7808|E‐mail: d.cutler@ucl.ac
ISTH Academy. Cutler D. Sep 4, 2018; 230973
Daniel Cutler
Daniel Cutler

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Background
Endothelial cells harbor specialized storage organelles, Weibel‐Palade bodies (WPBs). Exocytosis of WPB content into the vascular lumen initiates primary hemostasis, mediated by von Willebrand factor (VWF), and inflammation, mediated by several proteins including P‐selectin. During full fusion, secretion of this large hemostatic protein and smaller pro‐inflammatory proteins are thought to be inextricably linked.
Objective
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.
Methods
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.
Results
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 hemostasis than later events) and is activated by protein kinase C (PKC) isoforms.
Conclusions
Secretagogues differentially recruit the actomyosin ring, thus demonstrating one mechanism by which the prothrombotic 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.
Keyword(s)
exocytosis, hemostasis, inflammation, von Willebrand factor, Weibel‐Palade bodies
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