Fibroblast growth factor signaling mediates pulmonary endothelial glycocalyx reconstitution

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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
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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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.
American Journal of Respiratory Cell and Molecular Biology, 56, 727-737
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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.
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