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The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1
Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction....
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049398/ https://www.ncbi.nlm.nih.gov/pubmed/36982455 http://dx.doi.org/10.3390/ijms24065380 |
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author | Schulz, Annika Drost, Carolin C. Hesse, Bettina Beul, Katrin Boeckel, Göran R. Lukasz, Alexander Pavenstädt, Hermann Brand, Marcus Di Marco, Giovana S. |
author_facet | Schulz, Annika Drost, Carolin C. Hesse, Bettina Beul, Katrin Boeckel, Göran R. Lukasz, Alexander Pavenstädt, Hermann Brand, Marcus Di Marco, Giovana S. |
author_sort | Schulz, Annika |
collection | PubMed |
description | Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction. In vitro exposure of primary human umbilical vein endothelial cells to excess sFlt-1 decreased eGC height and increased stiffness as determined by atomic force microscopy (AFM). Yet, structural loss of the eGC components was not observed, as indicated by Ulex europaeus agglutinin I and wheat germ agglutinin staining. Moreover, the conformation observed under excess sFlt-1, a collapsed eGC, is flat and stiff with unchanged coverage and sustained content. Functionally, this conformation increased the endothelial adhesiveness to THP-1 monocytes by about 35%. Heparin blocked all these effects, but the vascular endothelial growth factor did not. In vivo administration of sFlt-1 in mice also resulted in the collapse of the eGC in isolated aorta analyzed ex vivo by AFM. Our findings show that excess sFlt-1 causes the collapse of the eGC and favors leukocyte adhesion. This study provides an additional mechanism of action by which sFlt-1 may cause endothelial dysfunction and injury. |
format | Online Article Text |
id | pubmed-10049398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100493982023-03-29 The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 Schulz, Annika Drost, Carolin C. Hesse, Bettina Beul, Katrin Boeckel, Göran R. Lukasz, Alexander Pavenstädt, Hermann Brand, Marcus Di Marco, Giovana S. Int J Mol Sci Article Soluble fms-like tyrosine kinase-1 (sFlt-1) is a secreted protein that binds heparan sulfate expressed on the endothelial glycocalyx (eGC). In this paper we analyze how excess sFlt-1 causes conformational changes in the eGC, leading to monocyte adhesion, a key event triggering vascular dysfunction. In vitro exposure of primary human umbilical vein endothelial cells to excess sFlt-1 decreased eGC height and increased stiffness as determined by atomic force microscopy (AFM). Yet, structural loss of the eGC components was not observed, as indicated by Ulex europaeus agglutinin I and wheat germ agglutinin staining. Moreover, the conformation observed under excess sFlt-1, a collapsed eGC, is flat and stiff with unchanged coverage and sustained content. Functionally, this conformation increased the endothelial adhesiveness to THP-1 monocytes by about 35%. Heparin blocked all these effects, but the vascular endothelial growth factor did not. In vivo administration of sFlt-1 in mice also resulted in the collapse of the eGC in isolated aorta analyzed ex vivo by AFM. Our findings show that excess sFlt-1 causes the collapse of the eGC and favors leukocyte adhesion. This study provides an additional mechanism of action by which sFlt-1 may cause endothelial dysfunction and injury. MDPI 2023-03-11 /pmc/articles/PMC10049398/ /pubmed/36982455 http://dx.doi.org/10.3390/ijms24065380 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Article Schulz, Annika Drost, Carolin C. Hesse, Bettina Beul, Katrin Boeckel, Göran R. Lukasz, Alexander Pavenstädt, Hermann Brand, Marcus Di Marco, Giovana S. The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title | The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title_full | The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title_fullStr | The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title_full_unstemmed | The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title_short | The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1 |
title_sort | endothelial glycocalyx as a target of excess soluble fms-like tyrosine kinase-1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10049398/ https://www.ncbi.nlm.nih.gov/pubmed/36982455 http://dx.doi.org/10.3390/ijms24065380 |
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