Biosynthesis of von Willebrand factor
Group leader: Ruben Bierings PhD
Biosynthesis of Von Willebrand factor (VWF) occurs in vascular endothelial cells and megakaryocytes. In endothelial cells VWF is stored in rod-shaped endothelial cell-specific storage organelles, the Weibel-Palade bodies. Besides VWF, these Weibel-Palade bodies contain a number of other proteins, including P-selectin, angiopoietin-2, osteoprotegerin and a number of other components. We have recently identified insulin growth factor binding protein 7 (IGFBP7) as a novel component of Weibel-Palade bodies (Van Breevoort et al., 2012) using mass spectrometry. Upon stimulation of endothelial cells by agonist such as thrombin or epinephrine, Weibel-Palade bodies undergo exocytosis, resulting in the release or surface expression of their contents. Epinephrine-induced Weibel-Palade body release is dependent on signaling pathways that involve the Rap1 exchange factor Epac1 as well as the Rac1 exchange factor PREX1 (Van Hooren et al. 2012, 2014).
Endothelial cells can also be derived from as yet uncharacterized precursors present in peripheral blood (Martin-Ramirez et al., 2012). These so-called blood outgrowth endothelial cells (BOECs) are phenotypically similar to vascular endothelial cells, as revealed by their cobblestone morphology, the presence of endothelial cell-specific Weibel-Palade bodies and the expression of endothelial cell markers such as VE-cadherin. We have employed endothelial cells derived of an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploinsufficient EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that STXBP1 promotes exocytosis of Weibel-Palade bodies thereby controlling the local release of vaso-active substances in the bloodstream (Van Breevoort et al., 2014).
Figure 1A: Rod shaped Weibel-Palade bodies (green) in endothelial cells. The periphery of the cell is shown by staining for ß-catenin (red)
Figure 1B: Ultra-large VWF strings on the surface of endothelial cells. Stings are visualized by adhering bloodplatelets (arrowheads).
- Van Breevoort D, Snijders AP, Hellen N, Weckhuysen S, van Hooren KW, Eikenboom J, Valentijn K, Fernandez-Borja M, Ceulemans B, De Jonge P, Voorberg J, Hannah M, Carter T, Bierings R. STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a. Blood 2014; 123(20):3185-94.