Cargando…

APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis

Vascular homeostasis is impaired in various diseases thereby contributing to the progression of their underlying pathologies. The endothelial immediate early gene Apolipoprotein L domain-containing 1 (APOLD1) helps to regulate endothelial function. However, its precise role in endothelial cell biolo...

Descripción completa

Detalles Bibliográficos
Autores principales: Stritt, Simon, Nurden, Paquita, Nurden, Alan T., Schved, Jean-François, Bordet, Jean-Claude, Roux, Maguelonne, Alessi, Marie-Christine, Trégouët, David-Alexandre, Mäkinen, Taija, Giansily-Blaizot, Muriel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973481/
https://www.ncbi.nlm.nih.gov/pubmed/35638551
http://dx.doi.org/10.3324/haematol.2022.280816
_version_ 1784898534082871296
author Stritt, Simon
Nurden, Paquita
Nurden, Alan T.
Schved, Jean-François
Bordet, Jean-Claude
Roux, Maguelonne
Alessi, Marie-Christine
Trégouët, David-Alexandre
Mäkinen, Taija
Giansily-Blaizot, Muriel
author_facet Stritt, Simon
Nurden, Paquita
Nurden, Alan T.
Schved, Jean-François
Bordet, Jean-Claude
Roux, Maguelonne
Alessi, Marie-Christine
Trégouët, David-Alexandre
Mäkinen, Taija
Giansily-Blaizot, Muriel
author_sort Stritt, Simon
collection PubMed
description Vascular homeostasis is impaired in various diseases thereby contributing to the progression of their underlying pathologies. The endothelial immediate early gene Apolipoprotein L domain-containing 1 (APOLD1) helps to regulate endothelial function. However, its precise role in endothelial cell biology remains unclear. We have localized APOLD1 to endothelial cell contacts and to Weibel-Palade bodies (WPB) where it associates with von Willebrand factor (VWF) tubules. Silencing of APOLD1 in primary human endothelial cells disrupted the cell junction-cytoskeletal interface, thereby altering endothelial permeability accompanied by spontaneous release of WPB contents. This resulted in an increased presence of WPB cargoes, notably VWF and angiopoietin-2 in the extracellular medium. Autophagy flux, previously recognized as an essential mechanism for the regulated release of WPB, was impaired in the absence of APOLD1. In addition, we report APOLD1 as a candidate gene for a novel inherited bleeding disorder across three generations of a large family in which an atypical bleeding diathesis was associated with episodic impaired microcirculation. A dominant heterozygous nonsense APOLD1:p.R49* variant segregated to affected family members. Compromised vascular integrity resulting from an excess of plasma angiopoietin-2, and locally impaired availability of VWF may explain the unusual clinical profile of APOLD1:p.R49* patients. In summary, our findings identify APOLD1 as an important regulator of vascular homeostasis and raise the need to consider testing of endothelial cell function in patients with inherited bleeding disorders without apparent platelet or coagulation defects.
format Online
Article
Text
id pubmed-9973481
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Fondazione Ferrata Storti
record_format MEDLINE/PubMed
spelling pubmed-99734812023-03-01 APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis Stritt, Simon Nurden, Paquita Nurden, Alan T. Schved, Jean-François Bordet, Jean-Claude Roux, Maguelonne Alessi, Marie-Christine Trégouët, David-Alexandre Mäkinen, Taija Giansily-Blaizot, Muriel Haematologica Article - Coagulation & its Disorders Vascular homeostasis is impaired in various diseases thereby contributing to the progression of their underlying pathologies. The endothelial immediate early gene Apolipoprotein L domain-containing 1 (APOLD1) helps to regulate endothelial function. However, its precise role in endothelial cell biology remains unclear. We have localized APOLD1 to endothelial cell contacts and to Weibel-Palade bodies (WPB) where it associates with von Willebrand factor (VWF) tubules. Silencing of APOLD1 in primary human endothelial cells disrupted the cell junction-cytoskeletal interface, thereby altering endothelial permeability accompanied by spontaneous release of WPB contents. This resulted in an increased presence of WPB cargoes, notably VWF and angiopoietin-2 in the extracellular medium. Autophagy flux, previously recognized as an essential mechanism for the regulated release of WPB, was impaired in the absence of APOLD1. In addition, we report APOLD1 as a candidate gene for a novel inherited bleeding disorder across three generations of a large family in which an atypical bleeding diathesis was associated with episodic impaired microcirculation. A dominant heterozygous nonsense APOLD1:p.R49* variant segregated to affected family members. Compromised vascular integrity resulting from an excess of plasma angiopoietin-2, and locally impaired availability of VWF may explain the unusual clinical profile of APOLD1:p.R49* patients. In summary, our findings identify APOLD1 as an important regulator of vascular homeostasis and raise the need to consider testing of endothelial cell function in patients with inherited bleeding disorders without apparent platelet or coagulation defects. Fondazione Ferrata Storti 2022-05-31 /pmc/articles/PMC9973481/ /pubmed/35638551 http://dx.doi.org/10.3324/haematol.2022.280816 Text en Copyright© 2023 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article - Coagulation & its Disorders
Stritt, Simon
Nurden, Paquita
Nurden, Alan T.
Schved, Jean-François
Bordet, Jean-Claude
Roux, Maguelonne
Alessi, Marie-Christine
Trégouët, David-Alexandre
Mäkinen, Taija
Giansily-Blaizot, Muriel
APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title_full APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title_fullStr APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title_full_unstemmed APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title_short APOLD1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and Weibel-Palade bodies, while disrupting hemostasis
title_sort apold1 loss causes endothelial dysfunction involving cell junctions, cytoskeletal architecture, and weibel-palade bodies, while disrupting hemostasis
topic Article - Coagulation & its Disorders
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9973481/
https://www.ncbi.nlm.nih.gov/pubmed/35638551
http://dx.doi.org/10.3324/haematol.2022.280816
work_keys_str_mv AT strittsimon apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT nurdenpaquita apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT nurdenalant apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT schvedjeanfrancois apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT bordetjeanclaude apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT rouxmaguelonne apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT alessimariechristine apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT tregouetdavidalexandre apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT makinentaija apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis
AT giansilyblaizotmuriel apold1losscausesendothelialdysfunctioninvolvingcelljunctionscytoskeletalarchitectureandweibelpaladebodieswhiledisruptinghemostasis