ESPN 50th Annual Meeting

ESPN 2017


 
Role of von Willebrand Factor (VWF) in endothelial cell repair after complement activation
MAGDALENA RIEDL 1 DANIEL SCHLAM 1 DAMIEN NOONE 1 CHRISTOPH LICHT 1

1- THE HOSPITAL FOR SICK CHILDREN
 
Introduction:

Complement dysregulation on endothelial cells causes EC activation/injury and leads to thrombotic microangiopathy. Different from previous concepts, our data demonstrate that complement dysregulation does not result in EC death. The current study focuses on EC complement evasion strategies, especially plasma membrane (PM) repair. We particularly focused on von Willebrand Factor (VWF), a protein stored in EC Weibel-Palade bodies(WPB), which we recently identified as new complement regulator on ECs.

Material and methods:

Complement activation on ECs was induced via sensitization on blood outgrowth endothelial cells (BOECs) from healthy controls and patients with von Willebrand disease (VWD) lacking both VWF and their storage WPBs. FM1-43X dye and calcein release were used to determine PM integrity.

Results:

Complement activation resulted in PM insertion of C5b-9 pores in control and VWD BOECs resulting in rapid Ca2+ influx. In response, VWF was recruited to the EC surface via WPBs merging with the PM and releasing VWF multimers within 30-60 min. Importantly, control but not VWD BOECs resealed their PM within 30 min. In control BOECs known cellular mechanisms for PM repair (endocytosis, lysosomal recruitment) were not critically involved in PM repair.

Conclusions:

PM repair is a major strategy of ECs to overcome complement-mediated injury. Our study indicates a new mechanism: Ca2+-dependent VWF recruitment to the EC surface resulting in complement regulation and EC PM repair via WPBs. The understanding of the detailed mechanism warrants further investigation.