Altered storage and function of von Willebrand factor in human cardiac microvascular endothelial cells isolated from recipient transplant hearts

Meli, A. et al. (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), 4553. (doi: 10.3390/ijms24054553) (PMID:36901985) (PMCID:PMC10003102)

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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:Articles
Additional Information:TC was funded by the UK Medical Research Council under the program grant MC_PC_13053. P.B.R. and J.E.M. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2106 (P.B.R), FC001178 (J.E.M), the Wellcome Trust (CC2106 (P.B.R), FC001119 (J.E.M)), and the UK Medical Research Council (CC2106 (P.B.R), FC001119 (J.E.M)). R.B. is funded by grants from the Landsteiner Stichting voor Bloedtransfusie Research (LSBR-1707 and LSBR-2005). M.L.R. was supported by the British Heart Foundation (RG/06/004).
Glasgow Author(s) Enlighten ID:Streetley, Dr James
Creator Roles:
Streetley, J.Formal analysis, Investigation, Visualization, Writing – review and editing
Authors: Meli, A., McCormack, A., Conte, I., Chen, Q., Streetley, J., Rose, M. L., Bierings, R., Hannah, M. J., Molloy, J. E., Rosenthal, P. B., and Carter, T.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:International Journal of Molecular Sciences
ISSN (Online):1422-0067
Published Online:25 February 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in International Journal of Molecular Sciences 24(5): 4553
Publisher Policy:Reproduced under a Creative Commons License

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