Modeling cadmium-induced endothelial toxicity using human pluripotent stem cell-derived endothelial cells

Abstract Cadmium (Cd) is a harmful heavy metal that results in vascular diseases such as atherosclerosis. Prior evidence revealed that Cd induced endothelial cell (EC) death and dysfunction, supporting that ECs are a primary target of Cd-induced toxicity, and can cause severe pathologies of vascular diseases. However, the underlying mechanisms remain unclear. In this study, we investigated the mechanisms of Cd-induced endothelial toxicity in a human model system of H9 human pluripotent stem cell-derived endothelial cells (H9-ECs). We showed that H9-ECs were susceptible to CdCl 2 induction, leading to detrimental changes of cell structure and significantly elevated level of apoptosis. We demonstrated that CdCl 2 -treated H9-ECs gave rise to a clear EC dysfunction phenotype and significantly differential transcriptomic profile. Signaling pathway analysis revealed that P38 or ERK signaling pathway is critical to cadmium-induced EC apoptosis and dysfunction, and inhibition of P38 or ERK effectively rescued CdCl 2 -induced endothelial toxicity in H9-ECs. Conclusively, hPSC-ECs can be a reliable model to recapitulate the EC pathological features and transcriptomic profile, which may provide a unique platform for understanding the cellular and molecular mechanisms of Cd-induced endothelial toxicity and for identifying therapeutic drugs for Cd-induced vascular diseases.