Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells.

Francesco Ferraro,Mafalda Lopes Da Silva,Robin Ketteler,Hwee Kuan Lee,Daniel F Cutler,William Grimes,Janos Kriston-Vizi

doi:10.1038/srep32473

Francesco Ferraro, Mafalda Lopes Da Silva + Show 5 more

Open Access

https://doi.org/10.1038/srep32473

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Abstract

Changes in the size of cellular organelles are often linked to modifications in their function. Endothelial cells store von Willebrand Factor (vWF), a glycoprotein essential to haemostasis in Weibel-Palade bodies (WPBs), cigar-shaped secretory granules that are generated in a wide range of sizes. We recently showed that forcing changes in the size of WPBs modifies the activity of this cargo. We now find that endothelial cells treated with statins produce shorter WPBs and that the vWF they release at exocytosis displays a reduced capability to recruit platelets to the endothelial cell surface. Investigating other functional consequences of size changes of WPBs, we also report that the endothelial surface-associated vWF formed at exocytosis recruits soluble plasma vWF and that this process is reduced by treatments that shorten WPBs, statins included. These results indicate that the post-exocytic adhesive activity of vWF towards platelets and plasma vWF at the endothelial surface reflects the size of their storage organelle. Our findings therefore show that changes in WPB size, by influencing the adhesive activity of its vWF cargo, may represent a novel mode of regulation of platelet aggregation at the vascular wall.

Highlights

The relationship between an organelle’s size and its function has become recognized as an important element in the modulation of cellular behaviour, both in physiology and pathology[1,2,3]
VWF plays a multifaceted role in platelet adhesion and thrombus formation. von Willebrand Factor (vWF) is synthesized by endothelial cells and megakaryocytes and stored in platelets; experimental evidence shows that the endothelial vWF contribution to haemostasis outweighs that of platelets[10,11] Soluble plasma vWF, derived from ADAMTS13 processing of the highly multimerized vWF secreted from endothelial cells can bind to substratum-adhered vWF, a homotypic association regulated by shear stress[12,13]
Statin treatment of endothelial cells reduces the size of Weibel-Palade bodies (WPBs) and the length of platelet-decorated vWF strings

Summary

Introduction

The relationship between an organelle’s size and its function has become recognized as an important element in the modulation of cellular behaviour, both in physiology and pathology[1,2,3]. We found that at exocytosis mini-WPBs generate shorter platelet-decorated vWF strings on the endothelial surface These findings raised the possibility that endothelial cells may respond to physiological and pathological cues by modulating their haemostatic phenotype through changes in the size of these secretory organelles[21]. We find that statin treatment of cultured endothelial cells reduces the size of their WPBs, and like other treatments with the same effect, this impacts on both platelet recruitment and the recruitment of circulating plasma vWF to the endothelial surface These new results lend further support to the idea that WPB size can play a role in the regulation of platelet aggregation

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