eprintid: 10082089
rev_number: 22
eprint_status: archive
userid: 608
dir: disk0/10/08/20/89
datestamp: 2019-09-24 09:39:40
lastmod: 2021-10-04 01:24:12
status_changed: 2019-09-24 09:39:40
type: article
metadata_visibility: show
creators_name: McCormack, JJ
creators_name: Harrison-Lavoie, K
creators_name: Cutler, DF
title: Human endothelial cells size-select their secretory granules for exocytosis to modulate their functional output
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D77
keywords: Endothelial Cells, Exocytosis, Organelle Size, Weibel-Palade Bodies, von Willebrand Factor
note: This version is the author accepted manuscript . For information on re-use, please refer to the publisher’s terms and conditions.
abstract: BACKGROUND: The secretory granules of endothelial cells, Weibel-Palade bodies, are released in response to numerous extracellular signals. Their cargo is critical to many vascular functions including haemostasis and inflammation. This presents a fundamental problem; how can these cells initiate tailor-made responses from the release of a single type of organelle, each with similar cargo? Each cell contains Weibel-Palade bodies in a wide range of sizes, and we have shown that experimentally-shortening these organelles disproportionately reduces their ability to initiate haemostasis in vitro, leaving leukocyte recruitment unaffected. Could the production of this range of sizes underpin differential responses? OBJECTIVES: To determine whether different agonists drive the exocytosis of different sizes of Weibel-Palade bodies. METHODS: We used a high-throughput automated unbiased imaging workflow to analyse the sizes of Weibel-Palade bodies within HUVECs before and after agonist activation to determine changes in organelle size distributions. RESULTS: We found that a subset of agonists differentially evoke the release of the longest, most pro-haemostatic organelles. Inhibiting the release of these longest organelles by just 15% gives a fall of 60% in an assay of secreted VWF function. CONCLUSIONS: The size-selection of granules for exocytosis represents a novel layer of control, allowing endothelial cells to provide diverse responses to different signals via the release of a single type of organelle.
date: 2020-01
date_type: published
official_url: https://doi.org/10.1111/jth.14634
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1696399
doi: 10.1111/jth.14634
lyricists_name: Cutler, Daniel
lyricists_name: McCormack, Jessica
lyricists_id: DFCUT81
lyricists_id: JJMCC62
actors_name: Cutler, Daniel
actors_id: DFCUT81
actors_role: owner
full_text_status: public
publication: Journal of Thrombosis and Haemostasis
volume: 18
number: 1
pagerange: 243-254
event_location: England
issn: 1538-7836
citation:        McCormack, JJ;    Harrison-Lavoie, K;    Cutler, DF;      (2020)    Human endothelial cells size-select their secretory granules for exocytosis to modulate their functional output.                   Journal of Thrombosis and Haemostasis , 18  (1)   pp. 243-254.    10.1111/jth.14634 <https://doi.org/10.1111/jth.14634>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10082089/1/McCormack%20et%20al.pdf