Weibel-Palade body logistics Express delivery in the vasculature

Endothelial cells (ECs) form the inner lining of the entire vascular system and provide a highly dynamic interface between blood and the underlying tissue. ECs are critically involved in the regulation of hemostasis and inflammation and are the main players in the formation of new blood vessels. To perform these specialized functions, ECs store a cocktail of bioactive compounds in secretory granules called Weibel-Palade bodies (WPBs). The main component of these vesicles is the hemostatic protein von Willebrand factor (VWF), but WPBs also contain various inflammatory and angiogenic mediators. Upon vascular injury WPB contents are rapidly secreted into the vascular lumen through fusion of the WPB with the plasma membrane, a process called exocytosis. A large number of proteins has been implicated in the logistics of WPB cargo transport in ECs. However, we do not yet fully understand how express delivery of WPB cargo to the vascular lumen is regulated. An important group of regulators of vesicle trafficking and release in all cells is the large family of soluble NSF attachment receptor (SNARE) proteins. Several SNAREs and related proteins have previously been shown to regulate WPB exocytosis. The research described in this thesis aims to elaborate on this knowledge as well as to provide novel insights into how WPB release is regulated and how this controls the delivery of its hemostatic, angiogenic and inflammatory content to sites of vascular perturbation.