title: Fibroblast Growth Factor Signaling Mediates Pulmonary Endothelial Glycocalyx Reconstitution.
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.
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Yimu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Haeger
authors.affiliation: Departments of 2 Biology and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Suflita
authors.affiliation: 3 Chemistry, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Kyrie L
authors.initials: KL
authors.lastname: Dailey
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: James F
authors.initials: JF
authors.lastname: Colbert
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Joshay A
authors.initials: JA
authors.lastname: Ford
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Picon
authors.affiliation: 4 Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Stearman
authors.affiliation: 3 Chemistry, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Lei
authors.initials: L
authors.lastname: Lin
authors.affiliation: 3 Chemistry, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Liu
authors.affiliation: 3 Chemistry, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Han
authors.affiliation: 3 Chemistry, Rensselaer Polytechnic Institute, Troy, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.affiliation: 1 Department of Medicine, University of Colorado Denver, Aurora, Colorado.|5 Department of Medicine, Denver Health Medical Center, Denver, Colorado.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002432:Cecum / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019276:Glycocalyx / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D006706:Homeostasis; D008026:Ligation; D008168:Lung / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011677:Punctures; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D018805:Sepsis / Q000473:pathology; D015398:Signal Transduction; D000099058:Exostosin 1
chemical_list: D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D017351:N-Acetylglucosaminyltransferases; D011133:Polysaccharide-Lyases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D000099058:Exostosin 1; C021349:heparitinsulfate lyase
keywords: fibroblast growth factor; heparan sulfate; sepsis