Fibroblast growth factor signaling mediates pulmonary endothelial glycocalyx reconstitution
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Authors
Yang, Yimu
Haeger, Sarah M.
Suflita, Matthew A.
Zhang, Fuming
Dailey, Kyrie L.
Colbert, James F.
Ford, Joshay A.
Picon, Mario A.
Stearman, Robert S.
Lin, Lei
Issue Date
2017-06-01
Type
Article
Language
ENG
Keywords
Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
Alternative Title
Abstract
The endothelial glycocalyx is a heparan sulfate (HS)-rich endovascular structure critical to endothelial function. Accordingly, endothelial glycocalyx degradation during sepsis contributes to tissue edema and organ injury. We determined the endogenous mechanisms governing pulmonary endothelial glycocalyx reconstitution, and if these reparative mechanisms are impaired during sepsis. We performed intravital microscopy of wild-type and transgenic mice to determine the rapidity of pulmonary endothelial glycocalyx reconstitution after nonseptic (heparinase-III mediated) or septic (cecal ligation and puncture mediated) endothelial glycocalyx degradation. We used mass spectrometry, surface plasmon resonance, and in vitro studies of human and mouse samples to determine the structure of HS fragments released during glycocalyx degradation and their impact on fibroblast growth factor receptor (FGFR) 1 signaling, a mediator of endothelial repair. Homeostatic pulmonary endothelial glycocalyx reconstitution occurred rapidly after nonseptic degradation and was associated with induction of the HS biosynthetic enzyme, exostosin (EXT)-1. In contrast, sepsis was characterized by loss of pulmonary EXT1 expression and delayed glycocalyx reconstitution. Rapid glycocalyx recovery after nonseptic degradation was dependent upon induction of FGFR1 expression and was augmented by FGF-promoting effects of circulating HS fragments released during glycocalyx degradation. Although sepsis-released HS fragments maintained this ability to activate FGFR1, sepsis was associated with the downstream absence of reparative pulmonary endothelial FGFR1 induction. Sepsis may cause vascular injury not only via glycocalyx degradation, but also by impairing FGFR1/EXT1-mediated glycocalyx reconstitution.
Description
American Journal of Respiratory Cell and Molecular Biology, 56, 727-737
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
Full Citation
Fibroblast growth factor signaling mediates pulmonary endothelial glycocalyx reconstitution, Y. Yang, S. M. Haeger, M. A. Suflita, F. Zhang, K. L. Dailey, J. F. Colbert, J. A. Ford, M. A. Picon, R. Stearman, L. Lin, X. Liu, X. Han, R. J. Linhardt, E. P. Schmidt, American Journal of Respiratory Cell and Molecular Biology, 56, 727-737, 2017.
Publisher
Terms of Use
Journal
Volume
Issue
PubMed ID
DOI
ISSN
15354989
10441549
10441549