Endothelial Glycocalyx, Mucin, and Glycan: A Hierarchical Synthesis From Molecular Building Blocks to Supramolecular Functional Barriers

Glycans encode molecular information, but the endothelial glycocalyx is an organized, multicomponent supramolecular structure whose architecture integrates glycan cues into coherent vascular responses in vivo. The vascular endothelial glycocalyx (eGCX) is a flow‐conditioned, membrane‐coupled surface layer that mediates mechanotransduction, selective permeability control under the revised Starling principle, and anticoagulant and anti‐inflammatory functions central to hemostasis and thrombo‐inflammation. However, “glycocalyx” is often conflated with individual glycans or mucins, causing conceptual drift in study design, assay selection, and biomarker interpretation. Here, we provide a hierarchical synthesis that distinguishes glycans as molecular building blocks, mucins as specialized, densely O‐glycosylated glycoproteins (secreted gel‐forming or transmembrane), and the eGCX as a supramolecular assembly organized around membrane‐anchored proteoglycans bearing glycosaminoglycans and associated plasma constituents. Although glycocalyces exist on nearly all mammalian cells, this review focuses on the vascular eGCX. We explain why emergent eGCX functions—shear‐dependent signaling, nitric oxide pathways, molecular sieving, and local regulation of coagulation—cannot be inferred from glycan motifs or mucin expression alone. We also clarify how commonly used readouts measure distinct biological processes: imaging‐derived thickness and coverage, the perfused boundary region as a hydrodynamic exclusion index, and circulating shedding products such as syndecan‐1, hyaluronan, and heparan sulfate as systemic markers of endothelial injury. Anchoring terminology to hierarchy and matching assays to targets should improve reproducibility and clinically meaningful translation in vascular disease, sepsis, trauma, and diabetes.