Diabetes impacts endothelial Weibel-Palade body biogenesis and VWF secretion

Abstract

Diabetes is associated with endothelial dysfunction, impaired wound healing, and increased thrombotic risk, yet the impact of diabetes on endothelial secretory organelles remains poorly understood. Weibel-Palade bodies (WPBs) are specialised endothelial granules that store and release von Willebrand factor (VWF) and other vasoactive cargo essential for haemostasis, inflammation, and vascular repair. Here, we investigated how diabetic environments influence WPB biogenesis and VWF structure under physiologically relevant flow conditions. Acute exposure of endothelial cells to constant or fluctuating high glucose concentrations, designed to model diabetic glycaemic conditions, did not alter WPB number or morphology under either static or high laminar shear stress conditions. In contrast, primary endothelial cells derived from a diabetic donor exhibited reduced Akt and eNOS signalling, significantly fewer WPBs, reduced intracellular VWF content, and shorter stimulus-evoked VWF strings compared with non-diabetic endothelial cells. Although total cellular VWF levels were reduced, high molecular weight (HMW) VWF content within endothelial lysates was not significantly altered. Plasma from diabetic patients demonstrated elevated circulating VWF levels together with marked inter-patient heterogeneity in VWF multimer composition. These findings suggest that chronic diabetes-associated endothelial dysfunction, rather than hyperglycaemia alone, alters WPB biology and VWF handling. We propose that dysregulated basal endothelial secretion may deplete endothelial VWF stores, limiting appropriate stimulus-coupled WPB release during vascular injury and contributing to defective vascular repair in diabetes.