Iron oxide nanoparticles induce reversible endothelial-to-mesenchymal transition in vascular endothelial cells at acutely non-cytotoxic concentrations

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

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Iron oxide nanoparticles promote vascular endothelial cells survival from oxidative stress by enhancement of autophagy

Regenerative Biomaterials ◽

10.1093/rb/rbz024 ◽

2019 ◽

Vol 6 (4) ◽

pp. 221-229 ◽

Cited By ~ 3

Author(s):

Jimei Duan ◽

Jiuju Du ◽

Rongrong Jin ◽

Wencheng Zhu ◽

Li Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Iron Oxide ◽

Adjuvant Therapy ◽

Iron Oxide Nanoparticles ◽

Vascular Endothelial Cells ◽

Umbilical Vein ◽

Superparamagnetic Iron Oxide ◽

Disease Diagnosis ◽

Oxide Nanoparticles

Abstract Dextran-coated superparamagnetic iron oxide nanoparticles (Dex-SPIONs) are excellent magnetic resonance imaging contrast agents for disease diagnosis and therapy. They can be delivered to target tissues mainly though vascular endothelium cells, which are major targets of oxidative stress. In cardiovascular cells, autophagy serves primarily on a pro-survival approach that protects the cells from oxidative stress even some autophagy inducers have been developed for adjuvant therapy of cardiovascular disorders. Our study demonstrated that the nanoparticles could be taken up by human umbilical vein endothelial cells (HUVECs) without causing obvious cytotoxicity but triggering autophagy. Furthermore, our results revealed that Dex-SPIONs could enhance HUVECs survival and reverse the reduction of nitric oxide secretion under the condition of H2O2 damage. However, these effects could be diminished by the autophagy inhibitor. In particular, we discovered that Dex-SPIONs evoked autophagy in HUVECs by reducing the phosphorylation of PRAS40, an upstream regulator of autophagy initiation. These results suggested that Dex-SPIONs functions as an autophagic-related antioxidant in HUVECs which may be utilized as an adjuvant therapy to cardiovascular disease associated with oxidative stress.

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