Abstract
BackgroundIron oxide nanoparticles (IONPs) have been extensively studied in different biomedical fields. Recently, the non-cytotoxic concentration of IONPs induced cell-specific response raised concern of their safety. Endothelial cell exposure was unavoidable in their applications, while whether IONPs affect the phenotype of vascular endothelial cells is largely unknown. In this work, the effect of IONPs on endothelial-to-mesenchymal transition (EndMT) was investigated in vitro and in vivo.ResultsThe incubation with γ-Fe2O3 nanoparticles modified with polyglucose sorbitol carboxymethyether (PSC-Fe2O3) at non-cytotoxic concentration induced morphological changes of human umbilical vein endothelial cells (HUVECs) from cobblestone-like to spindle mesenchymal-like morphology, while PSC-Fe2O3 mostly stay in the culture medium and intercellular space. At the same time, the endothelial marker CD31 and VE-cadherin was decreased along with the inhibitory of angiogenesis properties of HUVEC. Meanwhile, the mesenchymal marker α-smooth muscle actin (α-SMA) and fibroblast specific protein (FSP) was up regulated significantly, and the migration ability of the cells was enhanced. When ROS scavenger mannitol or AA was supplemented, the EndMT was rescued. Results from the in vivo study showed that, expression of CD31 was decreased and α-SMA increased in the liver, spleen and kidney of mice given PSC-Fe2O3, and the density of collagen fibers in the liver sinusoid of mice was increased. The supplementary mannitol or AA could reverse the degree of EndMT in the tissues. Mechanistic study in vitro indicated that the level of extracellular hydroxyl radicals (·OH) was up regulated significantly by PSC-Fe2O3, which induced the response of intracellular ROS and resulted in the EndMT effect on HUVECs.ConclusionThe PSC-Fe2O3 was capable of inducing EndMT in the endothelial cells at acutely non-cytotoxic dose due to its intrinsic peroxidase-like activity, though they were few taken up by endothelial cell. The EndMT effect on HUVEC can be rescued by ROS scavenger in vitro and in vivo.
Highlights
Iron oxide nanoparticles (IONPs) have been extensively studied in different biomedical fields
It should be noted that polydextrose sorbitol carboxymethyl ether (PSC)-Fe2O3 did not show any cytotoxicity to Human umbilical vein endothelial cells (HUVEC) when its concentration was reached at 600 μg/mL (Fig. 1b), the morphology of the cells changed significantly, showing a spindle mesenchymal-like morphology at the concentration while losing their endothelial characteristic polygonal shape (Fig. 1c)
PSC-Fe2O3 induce endothelial-to-mesenchymal transition (EndMT) we investigated what happened on the phenotype of HUVECs when their morphology changed largely
Summary
Iron oxide nanoparticles (IONPs) have been extensively studied in different biomedical fields. The endothelial integrity was reported to alter via interplay with barrier function and attenuation of cytoprotective and anti-inflammatory NO production at noncytotoxic concentration of IONPs [9] These cues imply possible effects of IONPs at non-cytotoxic concentration on the phenotype of ECs. Endothelium to mesenchymal transition (EndMT) is one changed phenotype of endothelial cells that represents losing endothelial characteristics and gaining a mesenchymal phenotype [10], which have a significant role in some diseases, especially fibrosis in liver [11, 12], kidney [13], cardiac [14], and atherosclerosis [15], diabetes [16] and cancer [17]. Whether IONPs can induce EndMT is unknown and worthy to note
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