Lopes da Silva, M;
Cutler, DF;
(2016)
Von Willebrand Factor multimerization and the polarity of secretory pathways in endothelial cells.
Blood
, 128
(2)
pp. 277-285.
10.1182/blood-2015-10-677054.
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Abstract
The Von Willebrand factor (VWF) synthesised and secreted by endothelial cells is central to haemostasis and thrombosis, providing a multifunctional adhesive platform that brings together components needed for these processes. VWF secretion can occur from both apical and basolateral sides of endothelial cells, and from constitutive, basal and regulated secretory pathways, the latter two via Weibel-Palade bodies (WPB). Although the amount and structure of VWF is crucial to its function, the extent of VWF release, multimerization and polarity of the three secretory pathways have only been addressed separately and with conflicting results. We set out to clarify these relationships using polarized Human Umbilical Vein Endothelial Cells (HUVECs) grown on Transwell membranes. We found that regulated secretion of Ultra large (UL) molecular weight VWF predominantly occurred apically, consistent with a role in localised platelet capture in the vessel lumen. We found that constitutive secretion of low molecular weight (LMW) VWF is targeted basolaterally, toward the subendothelial matrix, using the adaptor protein complex 1 (AP-1), where it may provide the bulk of collagen bound subendothelial VWF. We also found that basally-secreted VWF is composed of UL-VWF, released continuously from WPBs in the absence of stimuli, and occurs predominantly apically, suggesting this could be the main source of circulating plasma VWF. Together, we provide a unified dataset reporting the amount and multimeric state of VWF secreted from the constitutive, basal and regulated pathways in polarized HUVECs, and have established a new role for AP-1 in the basolateral constitutive secretion of VWF.
| Type: | Article |
|---|---|
| Title: | Von Willebrand Factor multimerization and the polarity of secretory pathways in endothelial cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1182/blood-2015-10-677054 |
| Publisher version: | http://dx.doi.org/10.1182/blood-2015-10-677054 |
| Language: | English |
| Additional information: | Copyright © 2016 by The American Society of Hematology. All rights reserved. This research was originally published in Blood. Lopes da Silva, M; Cutler, DF; Von Willebrand Factor multimerization and the polarity of secretory pathways in endothelial cells. Blood, 2016; Vol: 128 (2) pp. 277-285 © the American Society of Hematology. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1490478 |
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