1. Dispatch and delivery at the ER–Golgi interface: how endothelial cells tune their hemostatic response
- Author
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Marije Kat, Coert Margadant, Jan Voorberg, Ruben Bierings, Graduate School, ACS - Microcirculation, Other Research, AII - Inflammatory diseases, Experimental Vascular Medicine, Landsteiner Laboratory, Medical oncology laboratory, and Cancer Center Amsterdam
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Weibel-Palade Bodies ,Von Willebrand disease ,Endothelial Cells ,Von Willebrand factor ,Cell Biology ,Biochemistry ,Hemostatics ,von Willebrand Diseases ,endoplasmic reticulum ,SNARE ,hemic and lymphatic diseases ,cardiovascular system ,Golgi ,endothelial cell ,Humans ,Weibel-Palade body ,GBF1 ,Molecular Biology ,STX5 ,circulatory and respiratory physiology ,SEC22B - Abstract
Von Willebrand factor (VWF) is a glycoprotein that is secreted into the circulation and controls bleeding by promoting adhesion and aggregation of blood platelets at sites of vascular injury. Substantial inter-individual variation in VWF plasma levels exists among the healthy population. Prior to secretion, VWF polymers are assembled and condensed into helical tubules, which are packaged into Weibel-Palade bodies (WPBs), a highly specialized post-Golgi storage compartment in vascular endothelial cells. In the inherited bleeding disorder Von Willebrand disease (VWD), mutations in the VWF gene can cause qualitative or quantitative defects, limiting protein function, secretion, or plasma survival. However, pathogenic VWF mutations cannot be found in all VWD cases. Although an increasing number of genetic modifiers have been identified, even more rare genetic variants that impact VWF plasma levels likely remain to be discovered. Here, we summarize recent evidence that modulation of the early secretory pathway has great impact on the biogenesis and release of WPBs. Based on these findings, we propose that rare, as yet unidentified quantitative trait loci influencing intracellular VWF transport contribute to highly variable VWF levels in the population. These may underlie the thrombotic complications linked to high VWF levels, as well as the bleeding tendency in individuals with low VWF levels.
- Published
- 2022