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Altered Storage and Function of von Willebrand Factor in Human Cardiac Microvascular Endothelial Cells Isolated from Recipient Transplant Hearts

Meli, A; McCormack, A; Conte, I; Chen, Q; Streetley, J; Rose, ML; Bierings, R; Hannah, MJ; Molloy, JE; Rosenthal, PB; et al. Meli, A; McCormack, A; Conte, I; Chen, Q; Streetley, J; Rose, ML; Bierings, R; Hannah, MJ; Molloy, JE; Rosenthal, PB; Carter, TD (2023) Altered Storage and Function of von Willebrand Factor in Human Cardiac Microvascular Endothelial Cells Isolated from Recipient Transplant Hearts. International Journal of Molecular Sciences, 24 (5). p. 4553. ISSN 1422-0067 https://doi.org/10.3390/ijms24054553
SGUL Authors: Carter, Thomas David

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Abstract

The assembly of von Willebrand factor (VWF) into ordered helical tubules within endothelial Weibel–Palade bodies (WPBs) is required for the efficient deployment of the protein at sites of vascular injury. VWF trafficking and storage are sensitive to cellular and environmental stresses that are associated with heart disease and heart failure. Altered storage of VWF manifests as a change in WPB morphology from a rod shape to a rounded shape and is associated with impaired VWF deployment during secretion. In this study, we examined the morphology, ultrastructure, molecular composition and kinetics of exocytosis of WPBs in cardiac microvascular endothelial cells isolated from explanted hearts of patients with a common form of heart failure, dilated cardiomyopathy (DCM; HCMECD), or from nominally healthy donors (controls; HCMECC). Using fluorescence microscopy, WPBs in HCMECC (n = 3 donors) showed the typical rod-shaped morphology containing VWF, P-selectin and tPA. In contrast, WPBs in primary cultures of HCMECD (n = 6 donors) were predominantly rounded in shape and lacked tissue plasminogen activator (t-PA). Ultrastructural analysis of HCMECD revealed a disordered arrangement of VWF tubules in nascent WPBs emerging from the trans-Golgi network. HCMECD WPBs still recruited Rab27A, Rab3B, Myosin-Rab Interacting Protein (MyRIP) and Synaptotagmin-like protein 4a (Slp4-a) and underwent regulated exocytosis with kinetics similar to that seen in HCMECc. However, secreted extracellular VWF strings from HCMECD were significantly shorter than for endothelial cells with rod-shaped WPBs, although VWF platelet binding was similar. Our observations suggest that VWF trafficking, storage and haemostatic potential are perturbed in HCMEC from DCM hearts.

Item Type: Article
Additional Information: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Keywords: 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences, Chemical Physics
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: International Journal of Molecular Sciences
ISSN: 1422-0067
Dates:
DateEvent
25 February 2023Published
22 February 2023Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MC_PC_13053Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
CC2106Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
CC2106Wellcome Trusthttp://dx.doi.org/10.13039/100004440
CC2106Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
FC001178Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
FC001119Wellcome Trusthttp://dx.doi.org/10.13039/100004440
FC001119Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
LSBR-1707Landsteiner Foundation for Blood Transfusion Researchhttp://dx.doi.org/10.13039/100009425
LSBR-2005Landsteiner Stichting voor Bloedtransfusie Researchhttp://dx.doi.org/10.13039/100009425
RG/06/004British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: https://openaccess.sgul.ac.uk/id/eprint/115198
Publisher's version: https://doi.org/10.3390/ijms24054553

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