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J Cell Sci. 2019 Feb 15;132(5). pii: jcs221952. doi: 10.1242/jcs.221952.

Synaptotagmin 5 regulates Ca2+-dependent Weibel-Palade body exocytosis in human endothelial cells.

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Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW18 ORE, UK.
MRC National Institute for Medical Research, London NW7 1AA, UK.
Microbiology Services Colindale, Public Health England, London, NW9 5EQ, UK.
Plasma Proteins, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, 1006 AD Amsterdam, PO Box 9190, The Netherlands.
Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW18 ORE, UK


Elevations of intracellular free Ca2+ concentration ([Ca2+]i) are a potent trigger for Weibel-Palade body (WPB) exocytosis and secretion of von Willebrand factor (VWF) from endothelial cells; however, the identity of WPB-associated Ca2+-sensors involved in transducing acute increases in [Ca2+]i into granule exocytosis remains unknown. Here, we show that synaptotagmin 5 (SYT5) is expressed in human umbilical vein endothelial cells (HUVECs) and is recruited to WPBs to regulate Ca2+-driven WPB exocytosis. Western blot analysis of HUVECs identified SYT5 protein, and exogenously expressed SYT5-mEGFP localised almost exclusively to WPBs. shRNA-mediated knockdown of endogenous SYT5 (shSYT5) reduced the rate and extent of histamine-evoked WPB exocytosis and reduced secretion of the WPB cargo VWF-propeptide (VWFpp). The shSYT5-mediated reduction in histamine-evoked WPB exocytosis was prevented by expression of shRNA-resistant SYT5-mCherry. Overexpression of SYT5-EGFP increased the rate and extent of histamine-evoked WPB exocytosis, and increased secretion of VWFpp. Expression of a Ca2+-binding defective SYT5 mutant (SYT5-Asp197Ser-EGFP) mimicked depletion of endogenous SYT5. We identify SYT5 as a WPB-associated Ca2+ sensor regulating Ca2+-dependent secretion of stored mediators from vascular endothelial cells.


Ca2+; Endothelial; Exocytosis; Secretion; Synaptotagmin; Weibel–Palade body


Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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