Iron 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. The 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. The 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.

中文翻译：

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氧化铁纳米粒子在急性非细胞毒性浓度下诱导血管内皮细胞中可逆的内皮细胞向间充质转化

氧化铁纳米粒子（IONPs）已在不同的生物医学领域进行了广泛的研究。最近，IONPs诱导的细胞特异性应答的非细胞毒性浓度引起了人们对其安全性的关注。内皮细胞暴露在其应用中是不可避免的，而IONPs是否会影响血管内皮细胞表型尚不清楚。在这项工作中，在体外和体内研究了IONPs对内皮向间充质转化（EndMT）的影响。在无细胞毒性浓度下用聚葡萄糖山梨糖醇羧甲基醚（PSC-Fe2O3）修饰的γ-Fe2O3纳米颗粒的孵育可诱导人脐静脉内皮细胞（HUVEC）的形态变化，从鹅卵石样变为纺锤体间充质样，而PSC-Fe2O3则多留在培养基和细胞间空间。同时，内皮标记物CD31和VE-钙黏着蛋白减少，同时抑制了HUVEC的血管生成特性。同时，间充质标记物α-平滑肌肌动蛋白（α-SMA）和成纤维细胞特异性蛋白（FSP）被上调，细胞迁移能力增强。当补充ROS清除剂甘露醇或AA时，EndMT被拯救。体内研究结果表明，给予PSC-Fe2O3的小鼠肝，脾和肾中CD31的表达降低，α-SMA升高，并且小鼠肝窦中的胶原纤维密度增加。补充甘露醇或AA可以逆转组织中EndMT的程度。体外机理研究表明，PSC-Fe2O3显着上调了细胞外羟基自由基（·OH）的水平，诱导细胞内ROS的反应并导致EndMT对HUVEC的作用。PSC-Fe 2 O 3由于其固有的过氧化物酶样活性而能够以急性无细胞毒性的剂量在内皮细胞中诱导EndMT，尽管它们很少被内皮细胞吸收。ROS清除剂可以在体内和体外挽救EndMT对HUVEC的作用。