Genomic instability and shear stress influence quantum dot-induced endothelial cell responses and gene expression

Abstract

Little is known about endothelial cell responses to nanoparticles under conditions simulating dysfunctional endothelium, a hallmark of vascular diseases, cancer, and aging. Endothelial genomic abnormalities and shear stress on the endothelial cells due to blood flow are key components of this microenvironment. Using organ-on-a-chip technologies and transcriptomics, we investigated the effects of genomic instability and shear stress on endothelial cell-level and RNA-level responses to model nanoparticles, CdSe/ZnS and InP/ZnS quantum dots (QDs). QDs were selected for their diagnostic potential, photostability enabling cellular tracking, and high uptake attributed to their ultrasmall size (13.9 and 3.9 nm). To model genomic instability, HUVEC cells were treated with monastrol (mt-HUVECs), and both control and mt-HUVEC models were exposed to 5 nM QD concentration. Transcriptomic analysis showed that Cdc20 gene was more downregulated in mt-HUVECs under dynamic flow (−5.68 vs dynamic HUVECs; −6.4 vs static mt-HUVECs), indicating a synergistic effect of flow and genomic instability on cell cycle suppression. Exposure to CdSe/ZnS QDs under dynamic conditions led to downregulation of the adherens junction pathway, which is consistent with the observed higher uptake and upregulation of heat shock and inflammatory response pathways. In contrast, InP/ZnS QDs upregulated tight junctions, explaining their lower uptake. Both QDs induced apoptotic pathway upregulation, with CdSe/ZnS QDs having more detrimental effects on viability. Combining genomic instability and shear stress resulted in different cell phenotypes that led to distinct cell responses and cell uptake of QDs. These findings guide future studies to better characterize endothelial responses to nanoparticles under biologically relevant conditions.