Low oscillatory shear stress regulates Weibel-Palade body size and vWF release

Abstract

AbstractBlood flow regulates vascular function by generating wall shear stress which impacts endothelial cell (EC) physiology. Whilst high laminar shear stress (HSS) maintains the functional integrity of the vasculature, low oscillatory shear stress (LOSS) evokes secretion of pro-thrombotic and pro-inflammatory components from ECs, thus promoting the development of cardiovascular disease (CVD). Pro-thrombotic and pro-inflammatory cargo are readily stored in endothelial-specific organelles termed Weibel-Palade bodies (WPBs). WPBs form purely due to the multimerization of the pro-thrombotic glycoprotein von Willebrand factor (vWF). Here we investigated if aberrant shear stress, induced by non-uniform oscillatory flow, modulates the biogenesis of WPBs, and the subsequent release of vWF. Ultimately, we demonstrate, using anin vitromodel, that LOSS has no effect on the level of vWF expression, however, LOSS promotes endothelial thrombotic potential by increasing WPB size, which impacts the length of the vWF strings that are released upon stimulation. Thus, wall shear stress can confer functional plasticity to WPBs by manipulating their biogenesis. Further understanding of the underlying mechanisms could aid generation of novel therapeutics in CVD.