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

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.

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A novel Munc13-4/S100A10/annexin A2 complex promotes Weibel–Palade body exocytosis in endothelial cells

Molecular Biology of the Cell ◽

10.1091/mbc.e17-02-0128 ◽

2017 ◽

Vol 28 (12) ◽

pp. 1688-1700 ◽

Cited By ~ 16

Author(s):

Tarek Chehab ◽

Nina Criado Santos ◽

Anna Holthenrich ◽

Sophia N. Koerdt ◽

Jennifer Disse ◽

...

Keyword(s):

Endothelial Cells ◽

Plasma Membrane ◽

Secretory Granules ◽

Annexin A2 ◽

Familial Hemophagocytic Lymphohistiocytosis ◽

Vessel Injury ◽

Membrane Tethering ◽

Membrane Contact ◽

Von Willebrand ◽

Willebrand Factor

Endothelial cells respond to blood vessel injury by the acute release of the procoagulant von Willebrand factor, which is stored in unique secretory granules called Weibel–Palade bodies (WPBs). Stimulated WPB exocytosis critically depends on their proper recruitment to the plasma membrane, but factors involved in WPB–plasma membrane tethering are not known. Here we identify Munc13-4, a protein mutated in familial hemophagocytic lymphohistiocytosis 3, as a WPB-tethering factor. Munc13-4 promotes histamine-evoked WPB exocytosis and is present on WPBs, and secretagogue stimulation triggers an increased recruitment of Munc13-4 to WPBs and a clustering of Munc13-4 at sites of WPB–plasma membrane contact. We also identify the S100A10 subunit of the annexin A2 (AnxA2)-S100A10 protein complex as a novel Munc13-4 interactor and show that AnxA2-S100A10 participates in recruiting Munc13-4 to WPB fusion sites. These findings indicate that Munc13-4 supports acute WPB exocytosis by tethering WPBs to the plasma membrane via AnxA2-S100A10.

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Annexins A2 and A8 in endothelial cell exocytosis and the control of vascular homeostasis

Biological Chemistry ◽

10.1515/hsz-2016-0207 ◽

2016 ◽

Vol 397 (10) ◽

pp. 995-1003 ◽

Cited By ~ 10

Author(s):

Volker Gerke

Keyword(s):

Endothelial Cells ◽

Blood Vessel ◽

Secretory Granules ◽

Von Willebrand Disease ◽

Factors Affecting ◽

Vascular Homeostasis ◽

Regulatory Circuits ◽

Vessel Injury ◽

Inflammatory Processes ◽

Von Willebrand

Abstract Blood vessel homeostasis is controlled by a variety of regulatory circuits that involve both the vessel-lining endothelial cells as well as the circulating blood cells and products thereof. One important feature is the control exerted by endothelial cells through regulated exocytosis of factors affecting blood coagulation and local inflammatory processes. These factors include two important adhesion proteins: the leukocyte receptor P-selectin and the pro-coagulant von Willebrand factor (VWF) that binds platelets and is involved in the formation of a platelet plug at sites of blood vessel injury. Failure to correctly produce and secrete P-selectin and VWF leads to pathologies such as von Willebrand disease, the most common inherited bleeding disorder. P-selectin and VWF are stored in unique secretory granules, the Weibel-Palade bodies (WPB), that undergo a complex maturation process and are acutely secreted following endothelial stimulation, e.g. in the course of inflammation or following blood vessel injury. Two annexins have been shown to be involved in different aspects of WPB biology: annexin A8 is required for proper WPB maturation and annexin A2 participates in late steps of WPB exocytosis. Thus, by affecting the stimulated release of P-selectin and VWF from endothelial cells, annexins fulfil important functions in the control of vascular homeostasis and could be considered as targets for influencing P-selectin- and VWF-dependent processes/pathologies.

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Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

Scientific Reports ◽

10.1038/srep32473 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 17

Author(s):

Francesco Ferraro ◽

Mafalda Lopes da Silva ◽

William Grimes ◽

Hwee Kuan Lee ◽

Robin Ketteler ◽

...

Keyword(s):

Endothelial Cells ◽

Von Willebrand Factor ◽

Secretory Granules ◽

Vascular Wall ◽

Endothelial Cell Surface ◽

Endothelial Surface ◽

Wide Range ◽

Storage Organelle ◽

Von Willebrand ◽

Willebrand Factor

Abstract Changes in the size of cellular organelles are often linked to modifications in their function. Endothelial cells store von Willebrand Factor (vWF), a glycoprotein essential to haemostasis in Weibel-Palade bodies (WPBs), cigar-shaped secretory granules that are generated in a wide range of sizes. We recently showed that forcing changes in the size of WPBs modifies the activity of this cargo. We now find that endothelial cells treated with statins produce shorter WPBs and that the vWF they release at exocytosis displays a reduced capability to recruit platelets to the endothelial cell surface. Investigating other functional consequences of size changes of WPBs, we also report that the endothelial surface-associated vWF formed at exocytosis recruits soluble plasma vWF and that this process is reduced by treatments that shorten WPBs, statins included. These results indicate that the post-exocytic adhesive activity of vWF towards platelets and plasma vWF at the endothelial surface reflects the size of their storage organelle. Our findings therefore show that changes in WPB size, by influencing the adhesive activity of its vWF cargo, may represent a novel mode of regulation of platelet aggregation at the vascular wall.

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Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage

Blood ◽

10.1182/blood-2002-07-2281 ◽

2003 ◽

Vol 101 (4) ◽

pp. 1384-1391 ◽

Cited By ~ 32

Author(s):

Sandra L. Haberichter ◽

Paula Jacobi ◽

Robert R. Montgomery

Keyword(s):

Endothelial Cells ◽

Species Differences ◽

Intracellular Localization ◽

Von Willebrand Disease ◽

Healthy Individuals ◽

Furin Cleavage ◽

Storage Granules ◽

Von Willebrand ◽

Willebrand Factor

Von Willebrand factor (VWF) is synthesized in endothelial cells, where it is stored in Weibel-Palade bodies. Administration of 1-desamino-8-D-arginine-vasopressin (DDAVP) to patients with type 1 von Willebrand disease and to healthy individuals causes a rapid increase in plasma VWF levels. This increase is the result of stimulated release of VWF from Weibel-Palade bodies in certain beds of endothelial cells. The VWF propeptide (VWFpp) targets VWF to storage granules through a noncovalent association. The nature of the VWFpp/VWF interaction was investigated by using cross-species differences in VWF storage. While canine VWFpp traffics to storage granules and facilitates the multimerization of human VWF, it does not direct human VWF to storage granules. Since storage takes place after furin cleavage, this defect appears to be due to the defective interaction of canine VWFpp and human VWF. To determine the regions within VWFpp and VWF important for this VWFpp/VWF association and costorage, a series of human-canine chimeric VWFpp and propeptide-deleted VWF (Δpro) constructs were produced and expressed in AtT-20 cells. The intracellular localization of coexpressed proteins was examined by confocal microscopy. Two amino acids, 416 in VWFpp and 869 in the mature VWF molecule, were identified as being critical for the association and granular storage of VWF.

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