title: Rab3D and annexin A2 play a role in regulated secretion of vWF, but not tPA, from endothelial cells.
abstract: von-Willebrand factor (vWF) and tissue-type plasminogen activator (tPA) are products of endothelial cells acutely released into the vasculature following cell activation. Both factors are secreted after intraendothelial Ca2+ mobilization, but exhibit opposing physiological effects with vWF inducing coagulation and tPA triggering fibrinolysis. To identify components that could regulate differentially the release of pro- and antithrombogenic factors, we analyzed the contribution of Rab3D and the annexin A2/S100A10 complex, proteins implicated in exocytotic events in other systems. We show that mutant Rab3D proteins interfere with the formation of bona fide Weibel-Palade bodies (WPbs), the principal storage granules of multimeric vWF, and consequently the acute, histamine-induced release of vWF. In contrast, neither appearance nor exocytosis of tPA storage granules is affected. siRNA-mediated downregulation of annexin A2/S100A10 and disruption of the complex by microinjection of peptide competitors result in a marked reduction in vWF but not tPA secretion, without affecting the appearance of WPbs. This indicates that distinct mechanisms underlie the acute secretion of vWF and tPA, enabling endothelial cells to fine-regulate the release of thrombogenic and fibrinolytic factors.
authors.affiliation: Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Münster, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Knop
authors.forename: Elin
authors.initials: E
authors.lastname: Aareskjold
authors.forename: Günther
authors.initials: G
authors.lastname: Bode
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
mesh_terms: D017306:Annexin A2 / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D004705:Endocytosis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D009418:S100 Proteins / Q000378:metabolism; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D006632:Histamine; D034741:RNA, Small Interfering; D009418:S100 Proteins; D010959:Tissue Plasminogen Activator; D020692:rab3 GTP-Binding Proteins; D014841:von Willebrand Factor; D000099248:S100 Calcium Binding Protein A10; C492134:RAB3D protein, human