Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease
Huiping Shi, Bojing Shao, Liang Gao, Thamizhiniyan Venkatesan, J. Michael McDaniel, Meixiang Zhou, Samuel McGee, Pengchun Yu, Jasimuddin Ahamed, Janna M. Journeycake, James N. George, Lijun Xia
Abstract
Vaso-occlusive episode (VOE) is a common and critical complication of sickle cell disease (SCD). Its pathogenesis is incompletely understood. von Willebrand factor (VWF), a multimeric plasma hemostatic protein synthesized and secreted by endothelial cells and platelets, is increased during a VOE. However, whether and how VWF contributes to the pathogenesis of VOE is not fully understood. In this study, we found increased VWF levels during tumor necrosis factor (TNF)-induced VOE in a humanized mouse model of SCD. Deletion of endothelial VWF decreased hemolysis, vascular occlusion, and organ damage caused by TNF-induced VOE in SCD mice. Moreover, administering ADAMTS13, the VWF-cleaving plasma protease, reduced plasma VWF levels, decreased inflammation and vaso-occlusion, and alleviated organ damage during VOE. These data suggest that promoting VWF cleavage via ADAMTS13 may be an effective treatment for reducing hemolysis, inflammation, and vaso-occlusion during VOE.