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....
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FB/Einrichtung: | FB 05: Medizinische Fakultät |
Dokumenttypen: | Artikel |
Medientypen: | Text |
Erscheinungsdatum: | 2023 |
Publikation in MIAMI: | 31.03.2023 |
Datum der letzten Änderung: | 31.03.2023 |
Angaben zur Ausgabe: | [Electronic ed.] |
Quelle: | International Journal of Molecular Sciences 24 (2023) 6, 5380, 1-15 |
Schlagwörter: | endothelial glycocalyx; soluble fms-like tyrosine kinase-1 (sFlt-1); heparin; endothelial dysfunction; endothelial injury; monocyte adhesion |
Fachgebiet (DDC): | 610: Medizin und Gesundheit |
Lizenz: | CC BY 4.0 |
Sprache: | English |
Förderung: | Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster). Förderer: Deutsche Forschungsgemeinschaft / Projektnummer: 418505912 |
Format: | PDF-Dokument |
URN: | urn:nbn:de:hbz:6-00089498666 |
Weitere Identifikatoren: | DOI: 10.17879/20089557337 |
Permalink: | https://nbn-resolving.de/urn:nbn:de:hbz:6-00089498666 |
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Onlinezugriff: | 10.3390_ijms24065380.pdf |
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.