Endothelial Barrier Dysfunction Induced by Zinc Oxide Nanoparticles <i>In</i> <i>Vivo</i> and <i>In</i> <i>Vitro</i> and Their Mechanism of Crossing the Endothelial Barrier

Abstract

In this study, the effects of zinc oxide nanoparticle (ZnO-NP) exposure on the endothelial barrier and the pathway of ZnO-NPs to cross the endothelial barrier were examined. C57 mice were exposed to ZnO-NPs (1.2 mg/kg and 6 mg/kg body weight) and ZnSO₄ (3.6 mg/kg). Zinc biodistribution and toxicity tests, including H&E staining, TUNEL and 8-OHdG IHC staining of highly vascularized organs (liver, kidney and spleen), were assessed. Endothelial barrier disruption was assessed by interendothelial junction IHC staining of the thoracic aorta, and was further studied in human umbilical vein endothelial cells (HUVECs). Four different kinds of endocytosis inhibitors were also used to study the endocytosis effects of the ZnO-NPs on the HUVECs. We found that a significantly increased concentration of zinc was detected in the highly vascularized organs from the ZnO-NP exposure groups, together with histopathologic changes such as higher apoptotic death and oxidative status. Interendothelial junction disruption and increased endothelial barrier permeability were found in both the <i>in vivo</i> and <i>in vitro</i> experiments. All four endocytosis inhibitors were able to reduce the uptake and transport of ZnO-NPs in the HUVECs. We concluded that ZnO-NPs may impair endothelial cells and induce endothelial barrier dysfunction and are able to cross the endothelial barrier through paracellular and transcellular routes.