Would you like email updates of new search results? (A) Conventional exocytosis in which single WPBs fuse with the plasma membrane, thereby releasing their cargo. Following recruitment of cargo at the TGN, there is a second wave of recruitment that delivers integral and peripheral membrane proteins to WPBs, some of which is AP3 dependent. Several Ca2+ binding proteins have been implicated in coupling these Ca2+ signals to regulated WPB exocytosis, including the above-mentioned Slp4-a, AnxA2 and Munc13-4 as well as another Munc13 family member, Munc13-2 (Zhou et al., 2016; Holthenrich et al., 2019); however, the actual WPB-associated Ca2+ sensor that could directly activate the SNARE machinery most likely is a member of the synaptotagmin family. PDF ADAMTS13: A New Link Between Thrombosis and Inflammation Multimerization, targeting, and tubulation for selected VWD mutations. Shape determined by immunofluorescence, in some cases confirmed by electron microscopy. Several other proteins are incorporated into WPBs in the TGN: tPA, angiopoietin-2, osteoprotegerin, and various cytokines, as well as P-selectin, a transmembrane protein with a large lumenal domain and short cytoplasmic tail. Introduction: lysosome-related organelles. eCollection 2022 Oct. El-Mansi S, Robinson CL, Kostelnik KB, McCormack JJ, Mitchell TP, Lobato-Mrquez D, Rajeeve V, Cutillas P, Cutler DF, Mostowy S, Nightingale TD. The .gov means its official. 8600 Rockville Pike Assembly of Weibel Palade body-like tubules from N-terminal - PNAS Changes in WPB structure appear to require prolonged exposure to monensin (1 hour), which may allow extensive changes in the tubular packing of VWF that do not occur over the relatively rapid formation and exocytosis of secretory pods (minutes). It follows that the rounding up of WPBs and particularly of large secretory pods could lead to the bulging of endothelial cells that might constrict blood flow or cause turbulence, especially in the microvasculature. and transmitted securely. Endothelial cells can actively control these surface properties by the regulated presentation of specific adhesion molecules. The exocyst complex in polarized exocytosis. Our fi ndings reveal an important role for ADAMTS13 in preventing excessive spontaneous Weibel-Palade body secretion, and in the regulation of leukocyte adhesion and extravasation during infl ammation. (2016). (C, D) Multigranular exocytosis where before exocytosis, WPBs coalesce into large intracellular membrane vesicles, termed secretory pods. These cigar-shaped membrane-bound structures function in both hemostasis and inflammation but their biogenesis is poorly understood. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Activation of Ral mediates assembly of the exocyst complex (4). Nightingale T. D., Pattni K., Hume A. N., Seabra M. C., Cutler D. F. (2009). A Two-Tier Golgi-Based Control of Organelle Size Underpins the Functional Plasticity of Endothelial Cells. (2002). Blood. Before Centre for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, Muenster, Germany, This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental Biology. These bodies function to store two principal molecules, P-selectin and Von Willebrand factor. Epub 2005 Jun 14. The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF. WPBs are endothelial cell-specific secretory organelles that, together with a long list of inflammatory and angiogenic mediators, store the hemostatic protein von Willebrand factor (VWF) as their main cargo. Upon demand, VWF is secreted into the blood circulation, where it unfolds into strings that capture platelets during the onset of primary hemostasis. Morphology of Weibel-Paladebodies. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Epub 2018 Aug 12. Sci Rep. 2016 Aug 31;6:32473. doi: 10.1038/srep32473. The tips of tubules frequently touch the WPB membrane, but the sides of tubules are separated from the membrane by a distance that often appears constant along the length of a tubule.3,23,47. Real-time imaging of the dynamics and secretory behavior of Weibel-Palade bodies. The role of von Willebrand factor in thrombus formation. Interactions between cell surface receptors and crosstalk between signaling pathways can fine-tune endothelial responses. surfactant-loaded lamellar bodies of alveolar epithelial cells (Miklavc et al., 2015), most likely require mechanical forces for efficient cargo expulsion. Tomosyn interacts with the t-SNAREs syntaxin4 and SNAP23 and plays a role in insulin-stimulated GLUT4 translocation. [2] Etymology [ edit] Weibel Palade Bodies: Unique Secretory Organelles of Endothelial Cells Your comment will be reviewed and published at the journal's discretion. Weibel-Palade body membrane proteins exhibit differential trafficking after exocytosis in endothelial cells. The content of multiple exocytosed WPBs may contribute to the formation of VWF strings. Copyright 2023, StatPearls Publishing LLC. The .gov means its official. (B) Lingering-kiss exocytosis is shown, where single WPBs fuse with the plasma membrane via a small fusion pore of approximately 12 nm in diameter.80 Because of the small size of the fusion pore, larger cargo proteins such as P-selectin and VWF are retained, whereas the smaller membrane-bound CD63 and soluble IL-8 are released. (for review see Sadler, 2008). The pH of the secretory pathway: measurement, determinants, and regulation. Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor. Preprint. (2014). However, in AtT-20 cells some recombinant VWF C1157F or C1234W was targeted to storage granules (Table 1).55. concerning unique maturation steps, cargo selection and Rab recruitment and the involvement of different actin structures in VWF release, remain to be answered. von Willebrand factor storage requires intact prosequence cleavage site. Epub 2005 Aug 8. eCollection 2022. 2015;10(10):e0140740. Cells. Exocytosis of Weibel-Palade bodies: how to unpack a vascular emergency Marked progress in understanding their biogenesis, intracellular transport and secretion has been made in the last decade revealing fascinating cell biological phenomena that drive the formation of the organelle and its many modes of exocytosis. Actomyosin II contractility expels von Willebrand factor from Weibel-Palade bodies during exocytosis, Regulator of G protein signalling 4 controls secretion of von Willebrand factor to the subendothelial matrix. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Activated platelets induce Weibel-Palade-body secretion and leukocyte rolling in vivo: role of P-selectin | Blood | American Society of Hematology Abstract. Arrowhead indicates a transport vesicle in close position to the WPB (WPB). Weibel Palade Bodies - StatPearls - NCBI Bookshelf However, exocytosis of single WPBs may prevail when the release of other WPB constituents is required, such as the exposure of P-selectin to initiate leukocyte binding. WPB are unique secretory organelles that allow vascular endothelial cells to respond rapidly to environmental changes by the secretion of factors that control hemostasis and inflammation. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD Depletion of BLOC-2 results in both, compromised LEL-to-WPB transport of CD63 and general WPB maturation defects with the WPB appearing round instead of elongated and clustered in the perinuclear region (Figure 1). Accessibility PMC Federal government websites often end in .gov or .mil. This suggests that syntaxin-3, most likely pairing with VAMP8 on another WPB, supports homotypic fusions of WPB that could occur during compound or cumulative exocytosis (Zupani et al., 2002; Valentijn et al., 2010; Kiskin et al., 2014; Stevenson et al., 2017) (Figure 1). Von Willebrand factor is essential for blood coagulation. Cell line listed was used to investigate VWF targeting and storage. Golgi origin of tubular inclusions in endothelial cells. Weibel-Palade bodies (WPBs) are the storage granules of endothelial cells, the cells that form the inner lining of the blood vessels and heart. Copyright 2023 by American Society of Hematology, Biosynthesis of VWF and the biogenesis of WPBs, Recruitment of other WPB cargo in the TGN, Mutations in VWD and defects in WPB biogenesis, Heterogenous WPBs enable specialized secretory responses, WPBs in the pathophysiology and treatment of disease, https://doi.org/10.1182/blood-2010-09-267492. The SNARE Sec22b was recently identified as another factor controlling WPB morphology presumably also by affecting the ER/Golgi transport route of VWF. The P-selectin lumenal domain alone is sufficient to direct incorporation into WPBs, possibly because it interacts with the DD3 domains of VWF.25 In addition, a YGVF motif in the P-selectin cytoplasmic tail can target heterologous proteins to WPBs. WPB formation is driven by von Willebrand factor, their most abundant protein, which controls both shape and size of WPBs. However, upon insult and endothelial cell activation surface properties change rapidly allowing leukocytes and platelets to adhere to the vessel wall. ScienceDirect is a registered trademark of Elsevier B.V. Maturing WPB acquire certain RabGTPases, e.g. As a consequence, this also reduces the pro-thrombotic activity of secreted VWF as VWF secretion from shorter WPB significantly dampens its platelet adhesion capability (Ferraro et al., 2016, 2020). Scale bar, 1 m. Maturation is accompanied by loss of the clathrin/AP-1 coat,22,23 aftiphilin, and -synergin,24 as well as a further decrease in pH to approximately pH 5.4.37 The separation between VWF tubules is relatively large within immature WPBs, which are much less electron dense than mature WPBs.3,23,38,39 The budding of clathrin-coated vesicles from immature WPBs probably removes selected proteins and facilitates condensation of mature WPB contents by removing excess membrane. Bethesda, MD 20894, Web Policies The VWF released from Weibel-Palade bodies consists of very high-molecular-weight VWF multimers that are the most active for binding to subendothelial tissue and in platelet-platelet interactions. About ScienceDirect Unauthorized use of these marks is strictly prohibited. Protein phosphatase 2B inhibition promotes the secretion of von Willebrand factor from endothelial cells. the tetraspanin and P selectin cofactor CD63) and most likely routed to the organelle by direct transport possibly involving tubular carriers. They include the RabGTPase Rab27a and the tetraspanin CD63 identifying WPB as lysosome-related organelles (LRO) that share molecular features with pigment-storing melanosomes (for reviews see Raposo et al., 2007; Bowman et al., 2019). A., Wilkie A. R., Fang C., Mendez L. M., et al. Federal government websites often end in .gov or .mil. Before As a library, NLM provides access to scientific literature. VWF tubules can extend the entire length of a WPB but are sometimes truncated (Figure 2).3,47,48 Tubules within immature WPBs tend to be curved and disorganized, but in mature WPBs the tubules usually are regularly arranged, with a majority running parallel from end to end of the WPB.3,23,47 Tomographic reconstructions of entire WPBs indicate that VWF tubules gently twist inside the mature WPB, which could mean that tubules are spring-loaded. Lingering-kiss exocytosis of WPBs is characterized by the rounding up of the WPBs. The vascular environment can rapidly alter, and the speed with which responses to both physiological and pathological changes are required necessitates the existence of a highly responsive system. Han X., Li P., Yang Z., Huang X., Wei G., Sun Y., et al. Exocytosis of Weibel-Palade bodies: how to unpack a vascular emergency kit. They are found in arteries, capillaries, veins, and the endocardium, but notably not in the lymphatic vessels. VWF strings attach to the surface of endothelial cells and provide a platform for adhesion of platelets (Figure 6).88 In addition, VWF strings attach to collagen at sites of tissue injury.91 The mechanism by which VWF strings are anchored to the plasma membrane is still under debate, but integrin v3 and P-selectin are potential candidates for anchoring, and this attachment is shear dependent.89,90, The relationship between altered WPB-biogenesis and disease is quite direct in the case of VWD. Finally, it should be noted that WPB maturation is not only accompanied by tubulation and tight packing of VWF and the acquisition of additional protein contents, it also generates other morphological characteristics typical for LRO. Federal government websites often end in .gov or .mil. A Novel Munc13-4/S100A10/annexin A2 Complex Promotes Weibel-Palade Body Exocytosis in Endothelial Cells. This process of platelet adhesion is one of the first steps of clot formation and maturation. Blood. Riociguat inhibits ultra-large VWF string formation on pulmonary artery endothelial cells from chronic thromboembolic pulmonary hypertension patients. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Traffic. To do so, vascular endothelial cells are equipped with unique secretory organelles that store among other things leukocyte and platelet adhesion receptors to be released on demand. Cargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation. Rab-genome Analysis Reveals Novel Insights in Weibel-Palade Body Exocytosis. J Thromb Haemost. Several investigators have addressed sorting of the tetraspanin CD63 to WPBs. (B) Reconstruction of VWF tubules assembled in vitro at pH 6.2 from purified dimeric DD3 and D1D2 domains. Heterogeneous distribution of Weibel-Palade bodies and von Willebrand factor along the porcine vascular tree. Synaptotagmin-5 has recently emerged as an interesting candidate as it localizes to WPB and is required for histamine evoked WPB exocytosis and VWF secretion. Their dimensions and unique morphology are dictated by the main cargo VWF, a large glycoprotein synthesized and first processed in the ER (for references and recent crystal structure of the VWF DD3 domains see Dong et al., 2019). Beta-arrestins regulate a Ral-GDS Ral effector pathway that mediates cytoskeletal reorganization. The physiological function of von Willebrand's factor depends on its tubular storage in endothelial Weibel-Palade bodies. Mainly factors identified in the recent years have been included. Weibel Palade Bodies - PubMed The AP-1 effectors aftiphilin and -synergin are recruited to forming WPBs and exhibit partial colocalization with immature perinuclear WPBs. Correspondence: Dr J. Eikenboom, Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; e-mail: h.c.j.eikenboom@lumc.nl. National Library of Medicine 2005 Aug 15;170(4):627-36. doi: 10.1083/jcb.200503054. For each cytokine, the fraction recovered in WPBs was no greater than that of enhanced green fluorescent protein, < 5%. Mietkowska M., Schuberth C., Wedlich-Sldner R., Gerke V. (20191866). Functional architecture of Weibel-Palade bodies | Blood | American Several aspects of WPB size control and maturation have been addressed recently revealing novel and exciting connections. Multigranular Exocytosis of Weibel-Palade Bodies in Vascular Endothelial Cells. conditions, use of -, Nightingale TD, McCormack JJ, Grimes W, Robinson C, Lopes da Silva M, White IJ, Vaughan A, Cramer LP, Cutler DF. Almost 20 years later WPBs were shown to contain von Willebrand factor (VWF),4 a multimeric hemostatic protein that is secreted into the blood in response to a variety of agonists and mediates platelet adhesion at sites of vascular injury. The endothelium can quickly deliver bioactive molecules by regulated exocytosis of its secretory granules, the WeibelPalade bodies (WPBs). An AP-1/clathrin coat plays a novel and essential role in forming the Weibel-Palade bodies of endothelial cells. Tuning the endothelial response: differential release of exocytic cargos from Weibel-Palade bodies. A.V., and J.V. PLoS One. PMC Genetics of Hypercoagulable and Hypocoagulable States. 10.1182/blood-2014-10-608596 [Google Scholar] Nguyen T. T. N., Koerdt S. N., Gerke V. (2020). Inherited defects in VWF cause von Willebrand disease (VWD), the most common inherited bleeding disorder.5 Interestingly, VWF is also produced by megakaryocytes and platelets,6 the latter containing tubular structures similar to those found in WPBs but eccentrically localized in the -granule, and shown to be positive for VWF by immunogold EM techniques.7 In fact, VWF is the only protein readily detected in WPBs after biosynthetic labeling of endothelial cells.8 Several other proteins have been identified as constituents of WPBs including tissue-type plasminogen activator (tPA), P-selectin, interleukin-8 (IL-8), eotaxin-3, angiopoietin-2, osteoprotegerin, endothelin-1, endothelin-converting enzyme, and calcitonin gene-related peptide.9,10 In addition, clotting factor VIII is stored with VWF in the endothelial cells of some tissues such as lung.11,12 Therefore, WPBs contain a supply of mediators that could be deployed in response to signaling molecules or mechanical stress, allowing vascular endothelial cells to influence hemostasis, inflammation, angiogenesis, and vascular tone. A Functional variation in the arginine vasopressin 2 receptor and the regulation of von Willebrand factor secretion. The effects of epinephrine infusion in patients with von Willebrand's disease. This review summarizes the major advances made on the biogenesis and exocytosis of WPBs and places these recent discoveries in the context of von Willebrand disease. Sharda A. V., Barr A. M., Harrison J. Regulation of Weibel-Palade Body Exocytosis. Another unresolved issue concerns the regulation of the spatially restricted changes in cortical actin architecture, in particular the questions whether certain membrane lipids enriched at WPB fusion sites such as PI(4,5)P2 are involved and which molecular players organize the actin reorganization precisely at the sites where WPB fuse or have fused. Intracellular trafficking of factor VIII to von Willebrand factor storage granules. Future research in this exciting topic of cell biology has to tell and will likely also benefit pharmacological interventions of the pathway that could help controlling vascular VWF (and P-selectin) levels in pathophysiological scenarios (Karampini et al., 2020; El-Mansi and Nightingale, 2021). 2023 Feb 23;141(8):930-944. doi: 10.1182/blood.2022017419. Differential Cargo Mobilisation within Weibel-Palade Bodies after Transient Fusion with the Plasma Membrane. (B) Scanning EM of VWF strings at the surface of stimulated HUVECs displaying numerous branching VWF strings. Blood 2011; 117 (19): 50335043. The WPBs are in proximity of a secretory pod (SP) that is only partially shown. Karampini E., Petra E. Brgisser P. E., Jenny Olins J., Aat A. Mulder A. cookies. 2021 Sep 8;10(9):2351. doi: 10.3390/cells10092351. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. -. (A) Immunofluorescence image of a human umbilical vein endothelial cell (HUVEC) labeled with an antibody against VWF, revealing the numerous elongated WPBs throughout the cell. Three tubules stop halfway into the WPB (arrowheads) and 2 tubules display kinks (arrows). Scale bar, 200 nm. Analysis of intracellular storage and regulated secretion of 3 von Willebrand disease-causing variants of von Willebrand factor. J Cell Biol. Left, whole tubule demonstrating an outside diameter of 25 nm. Leebeek F. W. G., Eikenboom J. C. J. These complementary results imply that some interactions between D2 and D3 domains are dispensable for multimerization but necessary for targeting and tubular packing of VWF in WPBs.65. (2012). A special enrichment of certain PM phospholipids is indeed observed at WPB-PM fusion sites and inhibitor and depletion experiments suggest that PI(4,5)P2 and the PI(4,5)P2 producing PI4P 5-kinase are required for efficient histamine-evoked WPB exocytosis (Nguyen et al., 2020). WPB formation is driven by VWF that is produced at the ER and trafficked to the Golgi (1). Plasma Membrane Phosphatidylinositol (4,5)-bisphosphate Promotes Weibel-Palade Body Exocytosis. Content Delivery to Newly Forming Weibel-Palade Bodies Is Facilitated by Multiple Connections with the Golgi Apparatus. Thank you for submitting a comment on this article. Aftiphilin and gamma-synergin are required for secretagogue sensitivity of Weibel-Palade bodies in endothelial cells. Crossref Medline Google Scholar; 34 Arribas M, Cutler DF. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel-Palade bodies. Careers. 2018 Sep 25;2(18):2347-2357. However, a more complex mutation at the furin cleavage site, deletion 2269_2270delCT, results in alternative splicing across intron 17 and causes persistence of pro-VWF.12,62 When expressed in AtT-20 cells, this variant is targeted to storage granules, in contrast to the R763G mutation, indicating that the persistence of pro-VWF per se does not prevent granular storage. 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). by identifying the factor(s) promoting actin polymerisation into the ring/coat-like structures at fused WPB. Clipboard, Search History, and several other advanced features are temporarily unavailable. Careers. Differential Exocytosis from Human Endothelial Cells Evoked by High Intracellular Ca2+concentration, Frontiers in Cell and Developmental Biology.
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