The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner

Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclero...

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Autores principales:	Henrike Hoermann, Irena Krueger, Nadine Maurus, Friedrich Reusswig, Yi Sun, Christina Kohlmorgen, Maria Grandoch, Jens W. Fischer, Margitta Elvers
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	platelets biglycan GPVI thrombus formation hemostasis arterial thrombosis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/5c43e2d6a3f44573b8aef90150531d25
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spelling	oai:doaj.org-article:5c43e2d6a3f44573b8aef90150531d252021-11-25T17:54:03ZThe Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner10.3390/ijms2222121681422-00671661-6596https://doaj.org/article/5c43e2d6a3f44573b8aef90150531d252021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12168https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.Henrike HoermannIrena KruegerNadine MaurusFriedrich ReusswigYi SunChristina KohlmorgenMaria GrandochJens W. FischerMargitta ElversMDPI AGarticleplateletsbiglycanGPVIthrombus formationhemostasisarterial thrombosisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12168, p 12168 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	platelets biglycan GPVI thrombus formation hemostasis arterial thrombosis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	platelets biglycan GPVI thrombus formation hemostasis arterial thrombosis Biology (General) QH301-705.5 Chemistry QD1-999 Henrike Hoermann Irena Krueger Nadine Maurus Friedrich Reusswig Yi Sun Christina Kohlmorgen Maria Grandoch Jens W. Fischer Margitta Elvers The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
description	Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.
format	article
author	Henrike Hoermann Irena Krueger Nadine Maurus Friedrich Reusswig Yi Sun Christina Kohlmorgen Maria Grandoch Jens W. Fischer Margitta Elvers
author_facet	Henrike Hoermann Irena Krueger Nadine Maurus Friedrich Reusswig Yi Sun Christina Kohlmorgen Maria Grandoch Jens W. Fischer Margitta Elvers
author_sort	Henrike Hoermann
title	The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
title_short	The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
title_full	The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
title_fullStr	The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
title_full_unstemmed	The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner
title_sort	proteoglycan biglycan modulates platelet adhesion and thrombus formation in a gpvi-dependent manner
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5c43e2d6a3f44573b8aef90150531d25
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The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner

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