Exocytosis of Weibel–Palade bodies: how to unpack a vascular emergency kit

Abstract

Summary The blood vessel wall has a number of self‐healing properties, enabling it to minimize blood loss and prevent or overcome infections in the event of vascular trauma. Endothelial cells prepackage a cocktail of hemostatic, inflammatory and angiogenic mediators in their unique secretory organelles, the Weibel–Palade bodies (WPBs), which can be immediately released on demand. Secretion of their contents into the vascular lumen through a process called exocytosis enables the endothelium to actively participate in the arrest of bleeding and to slow down and direct leukocytes to areas of inflammation. Owing to their remarkable elongated morphology and their secretory contents, which span the entire size spectrum of small chemokines all the way up to ultralarge von Willebrand factor multimers, WPBs constitute an ideal model system for studying the molecular mechanisms of secretory organelle biogenesis, exocytosis, and content expulsion. Recent studies have now shown that, during exocytosis, WPBs can undergo several distinct modes of fusion, and can utilize fundamentally different mechanisms to expel their contents. In this article, we discuss recent advances in our understanding of the composition of the WPB exocytotic machinery and how, because of its configuration, it is able to support WPB release in its various forms.

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

“…Within platelets, vWF is packaged into alpha granules, while the circulatory endothelium stores the protein in Weibel‐Palade bodies (WPBs) . In addition to vWF, WPBs contain a host of factors that contribute to inflammation and angiogenesis, such as interleukin‐6, interleukin‐8, and angiopoietin‐2 . These molecules can be variably packaged, dependent upon cues from their surrounding microenvironment, such as shear force and chemical signaling.…”

Alternative trafficking of Weibel‐Palade body proteins in CRISPR/Cas9‐engineered von Willebrand factor–deficient blood outgrowth endothelial cells

“…Following its synthesis in ECs, VWF is stored in rod‐shaped storage organelles, called Weibel‐Palade bodies (WPBs), where it is stored together with a wide variety of inflammatory and angiogenic mediators . VWF is the driving force behind the formation of its own storage organelle, illustrated by the lack of WPBs in ECs from a patient with severe VWD type 3 or from VWF null animal models and the formation of pseudo‐WPBs upon heterologous expression of VWF in other cell types .…”

“…3 Following its synthesis in ECs, VWF is stored in rod-shaped storage organelles, called Weibel-Palade bodies (WPBs), where it is stored together with a wide variety of inflammatory and angiogenic mediators. [4][5][6] VWF is the driving force behind the formation of its own storage organelle, illustrated by the lack of WPBs in ECs from a patient with severe VWD type 3 7 or from VWF null animal models [8][9][10] and the formation of pseudo-WPBs upon heterologous expression of VWF in other cell types. [11][12][13] Upon endothelial triggering, that is, after vascular damage, WPBs undergo exocytosis and deliver their cargo to the cell surface or into the vascular lumen, leading to the formation of long VWF strings to which platelets and also leukocytes and erythrocytes can adhere.…”

Sec22b determines Weibel-Palade body length by controlling anterograde ER-Golgi transport

“…The LKO.1-puro-CMV-mEGFP-U6-shC002 vector, which simultaneously expresses mEGFP and a non-targeting control shRNA from the CMV and U6 promoter respectively, was described previously 32 . shRNAs targeting Sec22b, VAMP7 and YKT6 were obtained from the MISSION® shRNA library developed by TRC at the Broad Institute of MIT and Harvard 7 and distributed by Sigma-Aldrich ( Supplementary Table S2). Fragments containing the shRNA expression cassette from the shRNA library were transferred to the LKO.1-puro-CMV-mEGFP-U6 vector by SphI-EcoRI subcloning.…”

“…Biogenesis of LROs is crucial for the proper function of a wide variety of cells, their importance being well-highlighted by the fact that defective LRO formation results in a vast manifestation of clinical abnormalities that include bleeding, immunodeficiency, hypopigmentation and neurological defects 5 . Within the LRO family, Weibel-Palade bodies (WPBs) are the storage organelles of endothelial cells (ECs) 6,7 . WPBs primarily contain von Willebrand factor (VWF), a large multimeric hemostatic protein that serves a critical role in platelet adhesion and as chaperone for coagulation factor VIII 8 .…”