Endothelial Ext1 Is Essential for Glycocalyx Integrity and Inflammatory Resolution in Acute Lung Injury

ABSTRACT: The endothelial glycocalyx (eGCX) heparan sulfate (HS) is essential for vascular barrier function and inflammation regulation. To elucidate the endothelial cell-autonomous role of the HS synthase Ext1, we generated endothelial-specific Ext1-deficient mice (Ext1flox/flox; VE-cadherin–Cre) and performed endotoxin challenge experiments. Transcriptomic analysis of pulmonary endothelial cells revealed marked down-regulation of HS- and glycocalyx-related genes and up-regulation of immune activation pathways. Fluorescence imaging and dextran extravasation assays confirmed significant depletion of lectin- and HS-labeled glycocalyx and barrier dysfunction. Electron microscopy demonstrated severe baseline loss of luminal glycocalyx. Following LPS administration, Ext1-deficient mice exhibited altered cytokine kinetics, delayed clearance of neutrophils and CD11b⁺ myeloid cells, increased late-phase macrophage accumulation, and prolonged pulmonary edema, indicating impaired resolution of inflammation. Gene set enrichment analysis revealed up-regulation of leukocyte transendothelial migration, chemokine signaling, and VEGF pathways, consistent with sustained endothelial activation.

ORGANISM(S): Mus musculus

PROVIDER: GSE313973 | GEO | 2026/10/07

REPOSITORIES: GEO