Figure 4
Figure 4. Schematic representation of VWF secretion from endothelial cells. Following its synthesis and packaging in WPBs, VWF follows a complex pathway allowing intraendothelial storage combined with basal and regulated secretion. In recent years, many aspects of the molecular machinery that regulate these processes have been identified and this figure provides a schematic overview of the essential elements. (Step 1) The formation of VWF-containing ministacks and subsequent WPBs requires the presence of clathrin coat, the adaptor protein AP-1 and Dlg1. (Step 2) WPBs move around randomly within the endothelial cell along microtubules driven by a so-far-unidentified kinesin/dynein complex. (Step 3) Subsequently, WPBs adhere onto the filamentous actin network via a triple protein complex involving Rab27a, MyoVa, and MyRIP. WPBs also attract a series of other proteins involved in the secretory machinery, including Rab3, Rab15, Rab27a, Rab37, Munc13-4, and Slp4a. (Step 4) Secretion of the WPB content is preceded by sequential steps of tethering, docking, and priming before fusion with the cellular membrane. Specific protein complexes are involved in each of these steps (see boxes). (Step 5) Three types of secretion can be distinguished: (A) basal secretion, in which a single WPB fuses to the cellular membrane and releases its contents (both VWF and other WPB proteins). (B) On rare occasions, exposure to the extracellular environment causes a rapid deacidification of the organelle provoking the pH-dependent tubular VWF structure to collapse. Consequently, VWF is retained within the remainder of the WPB, whereas other WPB proteins (such as interleukin-8) are secreted into the circulation. This process is referred to as a lingering kiss. (C) Upon agonist-induced endothelial stimulation, multiple WPBs aggregate and might eventually fuse into a large secretory vesicle, referred to as secretory pods. This results in the release of massive amounts of VWF multimers. These multimers assemble into the long bundles (up to several hundred μm) that consist of multiple multimers. These bundles are highly thrombogenic as they efficiently recruit platelets. To reduce the thrombogenic potential of the platelet-decorated VWF strings, the action of ADAMTS13 (and also of plasmin under certain conditions) is required. This figure has been inspired by figures presented elsewhere.14,38,39

Schematic representation of VWF secretion from endothelial cells. Following its synthesis and packaging in WPBs, VWF follows a complex pathway allowing intraendothelial storage combined with basal and regulated secretion. In recent years, many aspects of the molecular machinery that regulate these processes have been identified and this figure provides a schematic overview of the essential elements. (Step 1) The formation of VWF-containing ministacks and subsequent WPBs requires the presence of clathrin coat, the adaptor protein AP-1 and Dlg1. (Step 2) WPBs move around randomly within the endothelial cell along microtubules driven by a so-far-unidentified kinesin/dynein complex. (Step 3) Subsequently, WPBs adhere onto the filamentous actin network via a triple protein complex involving Rab27a, MyoVa, and MyRIP. WPBs also attract a series of other proteins involved in the secretory machinery, including Rab3, Rab15, Rab27a, Rab37, Munc13-4, and Slp4a. (Step 4) Secretion of the WPB content is preceded by sequential steps of tethering, docking, and priming before fusion with the cellular membrane. Specific protein complexes are involved in each of these steps (see boxes). (Step 5) Three types of secretion can be distinguished: (A) basal secretion, in which a single WPB fuses to the cellular membrane and releases its contents (both VWF and other WPB proteins). (B) On rare occasions, exposure to the extracellular environment causes a rapid deacidification of the organelle provoking the pH-dependent tubular VWF structure to collapse. Consequently, VWF is retained within the remainder of the WPB, whereas other WPB proteins (such as interleukin-8) are secreted into the circulation. This process is referred to as a lingering kiss. (C) Upon agonist-induced endothelial stimulation, multiple WPBs aggregate and might eventually fuse into a large secretory vesicle, referred to as secretory pods. This results in the release of massive amounts of VWF multimers. These multimers assemble into the long bundles (up to several hundred μm) that consist of multiple multimers. These bundles are highly thrombogenic as they efficiently recruit platelets. To reduce the thrombogenic potential of the platelet-decorated VWF strings, the action of ADAMTS13 (and also of plasmin under certain conditions) is required. This figure has been inspired by figures presented elsewhere.14,38,39 

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