Abstract
Endothelial exocytosis regulates vascular thrombosis and inflammation. The trafficking and release of endothelial vesicles is mediated by SNARE (Soluble NSF Attachment protein REceptors) molecules, but the exact identity of endothelial SNAREs has been unclear. Three SNARE molecules form a ternary complex, including isoforms of the syntaxin (STX), vesicle-associated membrane protein (VAMP), and synaptosomal-associated protein (SNAP) families. We now identify SNAP23 as the predominant endothelial SNAP isoform that mediates endothelial exocytosis of von Willebrand Factor (VWF). SNAP23 was localized to the plasma membrane. Knockdown of SNAP23 decreased endothelial exocytosis, suggesting it is important for endothelial exocytosis. SNAP23 interacted with the endothelial exocytic machinery, and formed complexes with other known endothelial SNARE molecules. Taken together, these data suggest that SNAP23 is a key component of the endothelial SNARE machinery that mediates endothelial exocytosis.
Highlights
Endothelial cells (EC) maintain the integrity of the vasculature
We found that Human umbilical vein endothelial cells (HUVEC) express mRNAs for SNAP23, SNAP25, SNAP29, SNAP47, and SNAP91 (Fig 1A)
We found that SNAP23 is the most highly expressed synaptosomal-associated protein (SNAP) isoform in different types of human endothelial cells; SNAP23 is localized to the endothelial cell membrane; SNAP23 forms complexes with other endothelial SNARE molecules; and most importantly, deficiency of SNAP23, but not the other endothelial SNAP
Summary
EC undergo exocytosis, releasing numerous hemostatic and inflammatory mediators into the blood steam [1,2,3]. Von Willebrand factor (VWF), a glycoprotein involved in hemostasis, is the major constituent released from WPBs. After its release, VWF initiates platelet adherence to the vessel wall, triggering a cascade of events that leads to thrombosis [2, 4,5,6]. Numerous studies have shown an association between plasma VWF levels and the risk of cardiovascular events: patients with increased VWF levels suffer a higher incidence of major adverse cardiac events [7, 8]. Enhanced understanding of the release of VWF may lead to novel treatments for vascular diseases such as atherosclerosis, stroke, myocardial infarction, and thrombosis
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