Promoted coagulant activity and disrupted blood-brain barrier depending on phosphatidylserine externalization of red blood cells exposed to ZnO nanoparticles

Abstract

Zinc oxide nanoparticles (ZnO-NPs) are nanomaterials mainly produced and used worldwide. They translocate to circulatory systems from various exposure routes. While blood and endothelial cells are persistently exposed to circulating ZnO-NPs, the potential risks posed by ZnO-NPs to the cardiovascular system are largely unknown. Our study identified the potential risk of thrombosis and disturbance of the blood-brain barrier (BBB) by coagulant activity on red blood cells (RBCs) caused by ZnO-NPs. ZnO-NPs promoted the externalization of phosphatidylserine and the generation of microvesicles through an imbalance of intracellular mechanisms regulating procoagulant activity in human RBCs. The coagulation cascade leading to thrombin generation was promoted in ZnO-NPs-treated human RBCs. Combined with human RBCs, ZnO-NPs caused coagulant activity on isolated rat RBCs and rat venous thrombosis models. We identified the erythrophagocytosis of RBCs into brain endothelial cells via increased PS exposure induced by ZnO-NPs. Excessive erythrophagocytosis contributes to disrupting the BBB function of endothelial cells. ZnO-NPs increased the procoagulant activity of RBCs, causing venous thrombosis. Excessive erythrophagocytosis through ZnO-NPs-treated RBCs resulted in the dysfunction of BBB. Our study will help elucidate the potential risk ZnO-NPs exert on the cardiovascular system.