Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy

TY - JOUR

T1 - Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy

AU - Nicolay, Jan P

AU - Thorn, Verena

AU - Daniel, Christoph

AU - Amann, Kerstin

AU - Siraskar, Balasaheb

AU - Lang, Florian

AU - Hillgruber, Carina

AU - Goerge, Tobias

AU - Hoffmann, Stefan

AU - Gorzelanny, Christian

AU - Huck, Volker

AU - Mess, Christian

AU - Obser, Tobias

AU - Schneppenheim, Reinhard

AU - Fleming, Ingrid

AU - Schneider, Matthias F

AU - Schneider, Stefan W

PY - 2018/7/19

Y1 - 2018/7/19

N2 - Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.

AB - Microangiopathy with subsequent organ damage represents a major complication in several diseases. The mechanisms leading to microvascular occlusion include von Willebrand factor (VWF), notably the formation of ultra-large von Willebrand factor fibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to vascular occlusion is incompletely clarified. We investigated the platelet-independent interaction between stressed erythrocytes and ULVWFs and its consequences for microcirculation and organ function under dynamic conditions. In response to shear stress, erythrocytes interacted strongly with VWF to initiate the formation of ULVWF/erythrocyte aggregates via the binding of Annexin V to the VWF A1 domain. VWF-erythrocyte adhesion was attenuated by heparin and the VWF-specific protease ADAMTS13. In an in vivo model of renal ischemia/reperfusion injury, erythrocytes adhered to capillaries of wild-type but not VWF-deficient mice and later resulted in less renal damage. In vivo imaging in mice confirmed the adhesion of stressed erythrocytes to the vessel wall. Moreover, enhanced eryptosis rates and increased VWF binding were detected in blood samples from patients with chronic renal failure. Our study demonstrates that stressed erythrocytes have a pronounced binding affinity to ULVWFs. The discovered mechanisms suggest that erythrocytes are essential for the pathogenesis of microangiopathies and renal damage by actively binding to ULVWFs.

KW - Journal Article

U2 - 10.1038/s41598-018-28961-2

DO - 10.1038/s41598-018-28961-2

M3 - SCORING: Journal article

C2 - 30026593

VL - 8

SP - 10945

JO - SCI REP-UK

JF - SCI REP-UK

SN - 2045-2322

IS - 1

ER -