title: Selective release of molecules from Weibel-Palade bodies during a lingering kiss.
abstract: Exocytosis of specialized endothelial cell secretory organelles, Weibel-Palade bodies (WPBs), is thought to play an important role in regulating hemostasis and intravascular inflammation. The major WPB core proteins are Von Willebrand factor (VWF) and its propolypeptide (Proregion), constituting more than 95% of the content. Although the composition of the WPBs can be fine-tuned to include cytokines and chemokines (eg, interleukin-8 [IL-8] and eotaxin-3), it is generally assumed that WPB exocytosis is inextricably associated with secretion of VWF. Here we show that WPBs can undergo a form of exocytosis during which VWF and Proregion are retained while smaller molecules, such as IL-8, are released. Imaging individual WPBs containing fluorescent cargo molecules revealed that during weak stimulation approximately 25% of fusion events result in a failure to release VWF or Proregion. The WPB membrane protein P-selectin was also retained; however, the membrane tetraspannin CD63 was released. Accumulation or exclusion of extracellular fluorescent dextran molecules ranging from 3 kDa to 2 mDa show that these events arise due to the formation of a fusion pore approximately 12 nm in diameter. The pore behaves as a molecular filter, allowing selective release of WPB core and membrane proteins. WPB exocytosis is not inextricably associated with secretion of VWF.
authors.affiliation: Division of Molecular Neuroendocrinology, Medical Research Councils (MRC), National Institute for Medical Research, London, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Babich
authors.forename: Athinoula
authors.initials: A
authors.lastname: Meli
authors.forename: Laura
authors.initials: L
authors.lastname: Knipe
authors.forename: John E
authors.initials: JE
authors.lastname: Dempster
authors.forename: Paul
authors.initials: P
authors.lastname: Skehel
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hannah
authors.forename: Tom
authors.initials: T
authors.lastname: Carter
mesh_terms: D042783:Endothelial Cells / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000378:metabolism; D018613:Microscopy, Confocal; D013314:Stress, Mechanical; D020302:Weibel-Palade Bodies / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D014841:von Willebrand Factor; D049452:Green Fluorescent Proteins