Endothelial Surface Glycocalyx in Vascular Functions and Diseases

Endothelial cells (ECs), which form the inner lining of the vasculature, are perpetually exposed to mechanical stimuli from blood flow. Their capacity to sense and respond to these forces is essential for vascular homeostasis. A diverse array of mechanosensors operates on the EC surface, within the plasma membrane, and throughout the cytoskeleton. Among these, the endothelial surface glycocalyx (ESG)-uniquely positioned at the blood-endothelium interface and intimately linked to classical mechanosensory complexes-has emerged as a pivotal yet underappreciated regulator. Once viewed merely as a passive barrier, the ESG is now acknowledged as a primary mechanosensor that converts hemodynamic forces into biochemical signals critical for vascular health. This updated chapter from the first edition offers a comprehensive review of the ESG. We begin with its molecular composition, ultrastructural organization, and variable thickness, as elucidated by advanced imaging techniques such as immunolabeling, electron microscopy, and super-resolution microscopy. Next, we examine the ESG's biomechanical properties and its central role in endothelial mechanotransduction and barrier regulation. We then explore its dynamic remodeling in response to physiological and pathological stimuli, with a focus on degradation in major vascular diseases. ESG shedding is not only a hallmark but also a causal driver of pathophysiology in conditions including atherosclerosis, sepsis, diabetes, cancer metastasis, and COVID-19-associated endotheliopathy. Finally, we spotlight emerging diagnostic tools for evaluating ESG integrity and review promising therapeutic strategies to preserve or restore its structure and function.