The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1.
Int J Mol Sci
; 24(6)2023 Mar 11.
Article
in En
| MEDLINE
| ID: mdl-36982455
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Pre-Eclampsia
/
Vascular Endothelial Growth Factor Receptor-1
Limits:
Animals
/
Female
/
Humans
Language:
En
Year:
2023
Type:
Article