Weibel Palade Bodies: Unique Secretory Organelles of Endothelial Cells that Control Blood Vessel Homeostasis

Abstract

Vascular endothelial cells produce and release compounds regulating vascular tone, blood vessel growth and differentiation, plasma composition, coagulation and fibrinolysis, and also engage in interactions with blood cells thereby controlling hemostasis and acute inflammatory reactions. These interactions have to be tightly regulated to guarantee smooth blood flow in normal physiology, but also allow specific and often local responses to blood vessel injury and infectious or inflammatory insults. To cope with these challenges, endothelial cells have the remarkable capability of rapidly changing their surface properties from non-adhesive (supporting unrestricted blood flow) to adhesive (capturing circulating blood cells). This is brought about by the evoked secretion of major adhesion receptors for platelets (von-Willebrand factor, VWF) and leukocytes (P-selectin) which are stored in a ready-to-be-used form in specialized secretory granules, the Weibel-Palade bodies (WPB). WPB are unique, lysosome related organelles that form at the trans-Golgi network and further mature by receiving material from the endolysosomal system. Failure to produce correctly matured VWF and release it through regulated WPB exocytosis results in pathologies, most importantly von-Willebrand disease, the most common inherited blood clotting disorder. The biogenesis of WPB, their intracellular motility and their fusion with the plasma membrane are regulated by a complex interplay of proteins and lipids, involving Rab proteins and their effectors, cytoskeletal components as well as membrane tethering and fusion machineries. This review will discuss aspects of WPB biogenesis, trafficking and exocytosis focussing on recent findings describing factors contributing to WPB maturation, WPB-actin interactions and WPB-plasma membrane tethering and fusion.

Keywords: calcium; exocytosis; hemostasis; lysosome-related organelle; secretory organelles.

FIGURE 1

Scheme depicting the WPB itinerary in endothelial cells. WPB formation is driven by VWF that is produced at the ER and trafficked to the Golgi (1). WPB that bud from the TGN in an AP-1 and clathrin dependent process are then transported to the cell periphery along microtubules. This is accompanied by the BLOC-2 and annexin A8 dependent transfer of endosomal components such as CD63 and VAMP8 to WPB (2). Maturing WPB acquire certain RabGTPases, e.g. Rab27A and Rab3B/D, the former required for linking WPB at the cortical actin cytoskeleton (via MyRIP/MyoVc) and supporting exocytosis (via Slp4-a) (3). Secretagogue induced tethering at and fusion with the PM requires docking factors, such as the annexin A2/S100A10/Munc13-4 complex and a SNARE-based fusion machinery and can also involve compound and cumulative events (3, 4 and 5). Finally, post fusion actin rings have been observed that support the full release of highly multimeric VWF (6). Mainly factors identified in the recent years have been included.