Cellular stress induces erythrocyte assembly on intravascular von Willebrand factor strings and promotes microangiopathy
2018
Microangiopathywith subsequent organ damage represents a major complication in several diseases. The mechanisms leading to
microvascular occlusioninclude
von Willebrand factor(VWF), notably the formation of ultra-large
von Willebrand factorfibers (ULVWFs) and platelet aggregation. To date, the contribution of erythrocytes to
vascular occlusionis 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 aggregatesvia 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
microangiopathiesand renal damage by actively binding to ULVWFs.
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