Lifecycle of Weibel-Palade bodies

 

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Summary

Weibel-Palade bodies (WPBs) are rod or cigar-shaped secretory organelles that are formed by the vascular endothelium. They contain a diverse set of proteins that either function in haemostasis, inflammation, or angiogenesis. Biogenesis of the WPB occurs at the Golgi apparatus in a process that is dependent on the main component of the WPB, the haemostatic protein von Willebrand Factor (VWF). During this process the organelle is directed towards the regulated secretion pathway by recruiting the machinery that responds to exocytosis stimulating agonists. Upon maturation in the periphery of the cell the WPB recruits Rab27A which regulates WPB secretion. To date several signaling pathways have been found to stimulate WPB release. These signaling pathways can trigger several secretion modes including single WPB release and multigranular exocytosis. In this review we will give an overview of the WPB lifecycle from biogenesis to secretion and we will discuss several deficiencies that affect the WPB lifecycle.

Zusammenfassung

Weibel-Palade-Körperchen (WPK) sind längsovale sekretorische Organellen, die vom Gefäßendothel gebildet werden. Sie enthalten diverse Proteine, die an der Blutstillung, Entzündung bzw. Angiogenese beteiligt sind. Die Biogenese der WPK erfolgt im Golgi-Apparat. Der Prozess hängt vom Hämostase-Protein von-Willebrand-Faktor (VWF) ab, der den Hauptbestandteil der WPK bildet. Während dieses Prozesses werden die Organellen in Richtung des regulierten Sekretionspfades geleitet, indem der Mechanismus aktiviert wird, der durch Stimulation von Agonisten auf die Exozytose reagiert. Bei Reifung in der Zellperipherie rekrutiert das WPK Rab27A, das die WPK-Sekretion reguliert. Bisher sind mehrere Signalwege bekannt, die die WPK-Freisetzung stimulieren. Die Signalwege können verschiedene Sekretionsmodi auslösen, wie beispielsweise die einzelne WPK-Freisetzung und die multigranuläre Exozytose. Dieser Artikel enthält eine Übersicht über den WPK-Lebenszyklus von der Biogenese bis zur Sekretion. Wir besprechen außerdem mehrere Mängel, die den WPK-Lebenszyklus betreffen.

• References

• 1 Valentijn KM, Sadler JE, Valentijn JA. et al. Functional architecture of Weibel-Palade bodies. Blood 2011; 117: 5033-5043.
  CrossrefPubMedGoogle Scholar
• 2 Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015; 125: 2019-2028.
  CrossrefPubMedGoogle Scholar
• 3 Weibel ER, Palade GE. New Cytoplasmic Components in Arterial Endothelia. J Cell Biol 1964; 23: 101-112.
  CrossrefPubMedGoogle Scholar
• 4 Wagner DD, Olmsted JB, Marder VJ. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. J Cell Biol 1982; 95: 355-360.
  CrossrefPubMedGoogle Scholar
• 5 Huang RH, Wang Y, Roth R. et al. Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor. Proc Natl Acad Sci U S A 2008; 105: 482-487.
  CrossrefPubMedGoogle Scholar
• 6 Andre P, Denis CV, Ware J. et al. Platelets adhere to and translocate on von Willebrand factor presented by endothelium in stimulated veins. Blood 2000; 96: 3322-3328.
  CrossrefPubMedGoogle Scholar
• 7 Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost 2013; 11: 581-592.
  CrossrefPubMedGoogle Scholar
• 8 Fiedler U, Scharpfenecker M, Koidl S. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004; 103: 4150-4156.
  CrossrefPubMedGoogle Scholar
• 9 van Breevoort D, van Agtmaal EL, Dragt BS. et al. Proteomic screen identifies IGFBP7 as a novel component of endothelial cell-specific Weibel-Palade bodies. J Proteome Res 2012; 11: 2925-2936.
  CrossrefPubMedGoogle Scholar
• 10 McEver RP, Beckstead JH, Moore KL. et al. GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest 1989; 84: 92-99.
  CrossrefPubMedGoogle Scholar
• 11 Bonfanti R, Furie BC, Furie B, Wagner DD. PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. Blood 1989; 73: 1109-1112.
  PubMedGoogle Scholar
• 12 Shahani T, Covens K, Lavend’homme R. et al. Human liver sinusoidal endothelial cells but not hepatocytes contain factor VIII. J Thromb Haemost 2014; 12: 36-42.
  CrossrefPubMedGoogle Scholar
• 13 Shahani T, Lavend’homme R, Luttun A. et al. Activation of human endothelial cells from specific vascular beds induces the release of a FVIII storage pool. Blood 2010; 115: 4902-4909.
  CrossrefPubMedGoogle Scholar
• 14 Pan J, Dinh TT, Rajaraman A. et al. Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo. Blood 2016; 128: 104-109.
  CrossrefPubMedGoogle Scholar
• 15 Haberichter SL, Jozwiak MA, Rosenberg JB. et al. The von Willebrand factor propeptide (VWFpp) traffics an unrelated protein to storage. Arterioscler Thromb Vasc Biol 2002; 22: 921-926.
  CrossrefPubMedGoogle Scholar
• 16 Voorberg J, Fontijn R, Calafat J. et al. Biogenesis of von Willebrand factor-containing organelles in heterologous transfected CV-1 cells. EMBO J 1993; 12: 749-758.
  PubMedGoogle Scholar
• 17 Michaux G, Cutler DF. How to roll an endothelial cigar: the biogenesis of Weibel-Palade bodies. Traffic 2004; 05: 69-78.
  CrossrefPubMedGoogle Scholar
• 18 Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood 2000; 96: 1808-1815.
  PubMedGoogle Scholar
• 19 Wise RJ, Barr PJ, Wong PA. et al. Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. Proc Natl Acad Sci U S A 1990; 87: 9378-9382.
  CrossrefPubMedGoogle Scholar
• 20 Purvis AR, Sadler JE. A covalent oxidoreductase intermediate in propeptide-dependent von Willebrand factor multimerization. J Biol Chem 2004; 279: 49982-49988.
  CrossrefPubMedGoogle Scholar
• 21 Rehemtulla A, Kaufman RJ. Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes. Blood 1992; 79: 2349-2355.
  CrossrefPubMedGoogle Scholar
• 22 Mayadas T, Wagner DD, Simpson PJ. von Willebrand factor biosynthesis and partitioning between constitutive and regulated pathways of secretion after thrombin stimulation. Blood 1989; 73: 706-711.
  CrossrefPubMedGoogle Scholar
• 23 Lopes Mda Silva, Cutler DF. von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells. Blood 2016; 128: 277-285.
  CrossrefPubMedGoogle Scholar
• 24 Federici AB, Bader R, Pagani S. et al. Binding of von Willebrand factor to glycoproteins Ib and IIb/ IIIa complex: affinity is related to multimeric size. Br J Haematol 1989; 73: 93-99.
  CrossrefPubMedGoogle Scholar
• 25 Berriman JA, Li S, Hewlett LJ. et al. Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells. Proc Natl Acad Sci U S A 2009; 106: 17407-17412.
  CrossrefPubMedGoogle Scholar
• 26 Zhou YF, Eng ET, Nishida N. et al. A pH-regulated dimeric bouquet in the structure of von Willebrand factor. EMBO J 2011; 30: 4098-4111.
  CrossrefPubMedGoogle Scholar
• 27 Michaux G, Hewlett LJ, Messenger SL. et al. Analysis of intracellular storage and regulated secretion of 3 von Willebrand disease-causing variants of von Willebrand factor. Blood 2003; 102: 2452-2458.
  CrossrefPubMedGoogle Scholar
• 28 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci U S A 1992; 89: 3531-3535.
  CrossrefPubMedGoogle Scholar
• 29 Hannah MJ, Hume AN, Arribas M. et al. Weibel-Palade bodies recruit Rab27 by a content-driven, maturation-dependent mechanism that is independent of cell type. J Cell Sci 2003; 116: 3939-3948.
  CrossrefPubMedGoogle Scholar
• 30 Haberichter SL. von Willebrand factor propeptide: biology and clinical utility. Blood 2015; 126: 1753-1761.
  CrossrefPubMedGoogle Scholar
• 31 Verweij CL, Hart M, Pannekoek H. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. EMBO J 1987; 06: 2885-2890.
  PubMedGoogle Scholar
• 32 Rosnoblet C, Ribba AS, Wollheim CB. et al. Regulated von Willebrand factor (vWf) secretion is restored by pro-vWf expression in a transfectable endothelial cell line. Biochim Biophys Acta 2000; 1495: 112-119.
  CrossrefPubMedGoogle Scholar
• 33 Haberichter SL, Jacobi P, Montgomery RR. Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage. Blood 2003; 101: 1384-1391.
  CrossrefPubMedGoogle Scholar
• 34 Zenner HL, Collinson LM, Michaux G, Cutler DF. High-pressure freezing provides insights into Weibel-Palade body biogenesis. J Cell Sci 2007; 120: 2117-2125.
  CrossrefPubMedGoogle Scholar
• 35 Metcalf DJ, Nightingale TD, Zenner HL. et al. Formation and function of Weibel-Palade bodies. J Cell Sci 2008; 121: 19-27.
  CrossrefPubMedGoogle Scholar
• 36 Lui-Roberts WW, Collinson LM, Hewlett LJ. et al. An AP-1/clathrin coat plays a novel and essential role in forming the Weibel-Palade bodies of endothelial cells. J Cell Biol 2005; 170: 627-636.
  CrossrefPubMedGoogle Scholar
• 37 Valentijn KM, Valentijn JA, Jansen KA, Koster AJ. A new look at Weibel-Palade body structure in endothelial cells using electron tomography. J Struct Biol 2008; 161: 447-458.
  CrossrefPubMedGoogle Scholar
• 38 Ferraro F, Kriston-Vizi J, Metcalf DJ. et al. A twotier Golgi-based control of organelle size underpins the functional plasticity of endothelial cells. Dev Cell 2014; 29: 292-304.
  PubMedGoogle Scholar
• 39 Mourik MJ, Faas FG, Zimmermann H. et al. Content delivery to newly forming Weibel-Palade bodies is facilitated by multiple connections with the Golgi apparatus. Blood 2015; 125: 3509-3516.
  CrossrefPubMedGoogle Scholar
• 40 Lopes Mda Silva, O’Connor MN, Kriston-Vizi J. et al. Type II PI4-kinases control Weibel-Palade body biogenesis and von Willebrand factor structure in human endothelial cells. J Cell Sci 2016; 129: 2096-2105.
  CrossrefPubMedGoogle Scholar
• 41 Ferraro F, Lopes Mda Silva, Grimes W. et al. Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells. Sci Rep 2016; 06: 32473.
  CrossrefPubMedGoogle Scholar
• 42 van Agtmaal EL, Bierings R, Dragt BS. et al. The shear stress-induced transcription factor KLF2 affects dynamics and angiopoietin-2 content of Weibel-Palade bodies. PLoS One 2012; 07: e38399.
  CrossrefPubMedGoogle Scholar
• 43 Michaux G, Pullen TJ, Haberichter SL, Cutler DF. P-selectin binds to the D’-D3 domains of von Willebrand factor in Weibel-Palade bodies. Blood 2006; 107: 3922-3924.
  CrossrefPubMedGoogle Scholar
• 44 Padilla A, Moake JL, Bernardo A. et al. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 2004; 103: 2150-2156.
  CrossrefPubMedGoogle Scholar
• 45 Zannettino AC, Holding CA, Diamond P. et al. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. J Cell Physiol 2005; 204: 714-723.
  CrossrefPubMedGoogle Scholar
• 46 Bierings R, van den Biggelaar M, Kragt A. et al. Efficiency of von Willebrand factor-mediated targeting of interleukin-8 into Weibel-Palade bodies. J Thromb Haemost 2007; 05: 2512-2519.
  CrossrefPubMedGoogle Scholar
• 47 Harrison-Lavoie KJ, Michaux G, Hewlett L. et al. P-selectin and CD63 use different mechanisms for delivery to Weibel-Palade bodies. Traffic 2006; 07: 647-662.
  CrossrefPubMedGoogle Scholar
• 48 Kiskin NI, Hellen N, Babich V. et al. Protein mobilities and P-selectin storage in Weibel-Palade bodies. J Cell Sci 2010; 123: 2964-2975.
  CrossrefPubMedGoogle Scholar
• 49 Lui-Roberts WW, Ferraro F, Nightingale TD, Cutler DF. Aftiphilin and gamma-synergin are required for secretagogue sensitivity of Weibel-Palade bodies in endothelial cells. Mol Biol Cell 2008; 19: 5072-5081.
  CrossrefPubMedGoogle Scholar
• 50 Erent M, Meli A, Moisoi N. et al. Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells. J Physiol 2007; 583: 195-212.
  CrossrefPubMedGoogle Scholar
• 51 Vischer UM, Wagner DD. CD63 is a component of Weibel-Palade bodies of human endothelial cells. Blood 1993; 82: 1184-1191.
  PubMedGoogle Scholar
• 52 Doyle EL, Ridger V, Ferraro F. et al. CD63 is an essential cofactor to leukocyte recruitment by endothelial P-selectin. Blood 2011; 118: 4265-4273.
  CrossrefPubMedGoogle Scholar
• 53 Knipe L, Meli A, Hewlett L. et al. A revised model for the secretion of tPA and cytokines from cultured endothelial cells. Blood 2010; 116: 2183-2191.
  CrossrefPubMedGoogle Scholar
• 54 Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112: 957-964.
  CrossrefPubMedGoogle Scholar
• 55 van Buul-Wortelboer MF, Brinkman HJ, Reinders JH. et al. Polar secretion of von Willebrand factor by endothelial cells. Biochim Biophys Acta 1989; 1011: 129-133.
  CrossrefPubMedGoogle Scholar
• 56 Vischer UM, Wollheim CB. Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. Thromb Haemost 1997; 77: 1182-1188.
  Article in Thieme ConnectPubMedGoogle Scholar
• 57 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-190.
  CrossrefPubMedGoogle Scholar
• 58 Birch KA, Pober JS, Zavoico GB. et al. Calcium/calmodulin transduces thrombin-stimulated secretion: studies in intact and minimally permeabilized human umbilical vein endothelial cells. J Cell Biol 1992; 118: 1501-1510.
  CrossrefPubMedGoogle Scholar
• 59 Vischer UM, Barth H, Wollheim CB. Regulated von Willebrand factor secretion is associated with agonist-specific patterns of cytoskeletal remodeling in cultured endothelial cells. Arterioscler Thromb Vasc Biol 2000; 20: 883-891.
  CrossrefPubMedGoogle Scholar
• 60 Kaufmann JE, Oksche A, Wollheim CB. et al. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest 2000; 106: 107-116.
  CrossrefPubMedGoogle Scholar
• 61 Cleator JH, Zhu WQ, Vaughan DE, Hamm HE. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood 2006; 107: 2736-2744.
  CrossrefPubMedGoogle Scholar
• 62 van Hooren KW, van Breevoort D, Fernandez-Borja M. et al. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 1 regulates epinephrine-induced exocytosis of Weibel-Palade bodies. J Thromb Haemost 2014; 12: 273-281.
  CrossrefPubMedGoogle Scholar
• 63 van Hooren KW, van Agtmaal EL, Fernandez-Borja M. et al. The Epac-Rap1 signaling pathway controls cAMP-mediated exocytosis of Weibel-Palade bodies in endothelial cells. J Biol Chem 2012; 287: 24713-24720.
  CrossrefPubMedGoogle Scholar
• 64 Rondaij MG, Bierings R, van Agtmaal EL. et al. Guanine exchange factor RalGDS mediates exocytosis of Weibel-Palade bodies from endothelial cells. Blood 2008; 112: 56-63.
  CrossrefPubMedGoogle Scholar
• 65 Yang SX, Yan J, Deshpande SS. et al. Rac1 regulates the release of Weibel-Palade Bodies in human aortic endothelial cells. Chin Med J (Engl) 2004; 117: 1143-1150.
  PubMedGoogle Scholar
• 66 de Leeuw HP, Wijers-Koster PM, van Mourik JA, Voorberg J. Small GTP-binding protein RalA associates with Weibel-Palade bodies in endothelial cells. Thromb Haemost 1999; 82: 1177-1181.
  Article in Thieme ConnectPubMedGoogle Scholar
• 67 Kim KS, Park JY, Jou I, Park SM. Regulation of Weibel-Palade body exocytosis by alpha-synuclein in endothelial cells. J Biol Chem 2010; 285: 21416-21425.
  CrossrefPubMedGoogle Scholar
• 68 Knop M, Aareskjold E, Bode G, Gerke V. Rab3D and annexin A2 play a role in regulated secretion of vWF, but not tPA, from endothelial cells. EMBO J 2004; 23: 2982-2992.
  CrossrefPubMedGoogle Scholar
• 69 Brandherm I, Disse J, Zeuschner D, Gerke V. cAMP-induced secretion of endothelial von Willebrand factor is regulated by a phosphorylation/ dephosphorylation switch in annexin A2. Blood 2013; 122: 1042-1051.
  CrossrefPubMedGoogle Scholar
• 70 Conte IL, Hellen N, Bierings R. et al. Interaction between MyRIP and the actin cytoskeleton regulates Weibel-Palade body trafficking and exocytosis. J Cell Sci 2016; 129: 592-603.
  CrossrefPubMedGoogle Scholar
• 71 Rojo IPulido, Nightingale TD, Darchen F. et al. Myosin Va acts in concert with Rab27a and MyRIP to regulate acute von-Willebrand factor release from endothelial cells. Traffic 2011; 12: 1371-1382.
  CrossrefPubMedGoogle Scholar
• 72 Nightingale TD, Pattni K, Hume AN. et al. Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells. Blood 2009; 113: 5010-5018.
  CrossrefPubMedGoogle Scholar
• 73 Manneville JB, Etienne-Manneville S, Skehel P. et al. Interaction of the actin cytoskeleton with microtubules regulates secretory organelle movement near the plasma membrane in human endothelial cells. J Cell Sci 2003; 116: 3927-3938.
  CrossrefPubMedGoogle Scholar
• 74 Romani Tde Wit, Rondaij MG, Hordijk PL. et al. Real-time imaging of the dynamics and secretory behavior of Weibel-Palade bodies. Arterioscler Thromb Vasc Biol 2003; 23: 755-761.
  CrossrefPubMedGoogle Scholar
• 75 Rondaij MG, Bierings R, Kragt A. et al. Dyneindynactin complex mediates protein kinase A-dependent clustering of Weibel-Palade bodies in endothelial cells. Arterioscler Thromb Vasc Biol 2006; 26: 49-55.
  CrossrefPubMedGoogle Scholar
• 76 Bierings R, Hellen N, Kiskin N. et al. The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis. Blood 2012; 120: 2757-2767.
  CrossrefPubMedGoogle Scholar
• 77 Zografou S, Basagiannis D, Papafotika A. et al. A complete Rab screening reveals novel insights in Weibel-Palade body exocytosis. J Cell Sci 2012; 125: 4780-4790.
  CrossrefPubMedGoogle Scholar
• 78 Pulido IR, Jahn R, Gerke V. VAMP3 is associated with endothelial weibel-palade bodies and participates in their Ca(2+)-dependent exocytosis. Biochim Biophys Acta 2011; 1813: 1038-1044.
  CrossrefPubMedGoogle Scholar
• 79 van Breevoort D, Snijders AP, Hellen N. et al. STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a. Blood 2014; 123: 3185-3194.
  CrossrefPubMedGoogle Scholar
• 80 Fu J, Naren AP, Gao X. et al. Protease-activated receptor-1 activation of endothelial cells induces protein kinase Calpha-dependent phosphorylation of syntaxin 4 and Munc18c: role in signaling p-selectin expression. J Biol Chem 2005; 280: 3178-3184.
  CrossrefPubMedGoogle Scholar
• 81 Matsushita K, Morrell CN, Cambien B. et al. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell 2003; 115: 139-150.
  CrossrefPubMedGoogle Scholar
• 82 Sanders YV, van der Bom JG, Isaacs A. et al. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. J Thromb Haemost 2015; 13: 956-966.
  CrossrefPubMedGoogle Scholar
• 83 Smith NL, Chen MH, Dehghan A. et al. 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. Circulation 2010; 121: 1382-1392.
  CrossrefPubMedGoogle Scholar
• 84 Michaux G, Abbitt KB, Collinson LM. et al. The physiological function of von Willebrand’s factor depends on its tubular storage in endothelial Weibel-Palade bodies. Dev Cell 2006; 10: 223-232.
  CrossrefPubMedGoogle Scholar
• 85 Hannah MJ, Skehel P, Erent M. et al. Differential kinetics of cell surface loss of von Willebrand factor and its propolypeptide after secretion from Weibel-Palade bodies in living human endothelial cells. J Biol Chem 2005; 280: 22827-22830.
  CrossrefPubMedGoogle Scholar
• 86 Cookson EA, Conte IL, Dempster J. et al. Characterisation of Weibel-Palade body fusion by amperometry in endothelial cells reveals fusion pore dynamics and the effect of cholesterol on exocytosis. J Cell Sci 2013; 126: 5490-5499.
  CrossrefPubMedGoogle Scholar
• 87 Burgin-Maunder CS, Brooks PR, Russell FD. Omega-3 fatty acids modulate Weibel-Palade body degranulation and actin cytoskeleton rearrangement in PMA-stimulated human umbilical vein endothelial cells. Mar Drugs 2013; 11: 4435-4450.
  CrossrefPubMedGoogle Scholar
• 88 Babich V, Knipe L, Hewlett L. et al. Differential effect of extracellular acidosis on the release and dispersal of soluble and membrane proteins secreted from the Weibel-Palade body. J Biol Chem 2009; 284: 12459-12468.
  CrossrefPubMedGoogle Scholar
• 89 Babich V, Meli A, Knipe L. et al. Selective release of molecules from Weibel-Palade bodies during a lingering kiss. Blood 2008; 111: 5282-5290.
  CrossrefPubMedGoogle Scholar
• 90 Mourik MJ, Valentijn JA, Voorberg J. et al. von Willebrand factor remodeling during exocytosis from vascular endothelial cells. J Thromb Haemost 2013; 11: 2009-2019.
  CrossrefPubMedGoogle Scholar
• 91 Valentijn KM, van Driel LF, Mourik MJ. et al. Multigranular exocytosis of Weibel-Palade bodies in vascular endothelial cells. Blood 2010; 116: 1807-1816.
  CrossrefPubMedGoogle Scholar
• 92 Conte IL, Cookson E, Hellen N. et al. Is there more than one way to unpack a Weibel-Palade body?. Blood 2015; 126: 2165-2167.
  CrossrefPubMedGoogle Scholar
• 93 Lorenzi O, Frieden M, Villemin P. et al. Protein kinase C-delta mediates von Willebrand factor secretion from endothelial cells in response to vascular endothelial growth factor (VEGF) but not histamine. J Thromb Haemost 2008; 06: 1962-1969.
  CrossrefPubMedGoogle Scholar
• 94 Nightingale TD, White IJ, Doyle EL. et al. Actomyosin II contractility expels von Willebrand factor from Weibel-Palade bodies during exocytosis. J Cell Biol 2011; 194: 613-629.
  CrossrefPubMedGoogle Scholar
• 95 Haberichter SL, Merricks EP, Fahs SA. et al. Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 2005; 105: 145-152.
  CrossrefPubMedGoogle Scholar
• 96 Starke RD, Paschalaki KE, Dyer CE. et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood 2013; 121: 2773-2784.
  CrossrefPubMedGoogle Scholar
• 97 Wang JW, Bouwens EA, Pintao MC. et al. Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease. Blood 2013; 121: 2762-2772.
  CrossrefPubMedGoogle Scholar
• 98 Wang JW, Groeneveld DJ, Cosemans G. et al. Biogenesis of Weibel-Palade bodies in von Willebrand’s disease variants with impaired von Willebrand factor intrachain or interchain disulfide bond formation. Haematologica 2012; 97: 859-866.
  CrossrefPubMedGoogle Scholar
• 99 Deprez L, Weckhuysen S, Holmgren P. et al. Clinical spectrum of early-onset epileptic encephalopathies associated with STXBP1 mutations. Neurology 2010; 75: 1159-1165.
  CrossrefPubMedGoogle Scholar
• 100 Saitsu H, Kato M, Mizuguchi T. et al. De novo mutations in the gene encoding STXBP1 (MUNC18–1) cause early infantile epileptic encephalopathy. Nat Genet 2008; 40: 782-788.
  CrossrefPubMedGoogle Scholar