Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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The impact of manganese on vascular endothelium

  • Gustavo H. Oliveira‑Paula (Department of Molecular Pharmacology, Albert Einstein College of Medicine) ;
  • Airton C. Martins (Department of Molecular Pharmacology, Albert Einstein College of Medicine) ;
  • Beatriz Ferrer (Department of Molecular Pharmacology, Albert Einstein College of Medicine) ;
  • Alexey A. Tinkov (Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University) ;
  • Anatoly V. Skalny (Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University) ;
  • Michael Aschner (Department of Molecular Pharmacology, Albert Einstein College of Medicine)
  • Received : 2024.05.04
  • Accepted : 2024.07.26
  • Published : 2024.10.15
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Abstract

Manganese (Mn) is an essential trace element involved in various physiological processes, but excessive exposure may lead to toxicity. The vascular endothelium, a monolayer of endothelial cells within blood vessels, is a primary target of Mn toxicity. This review provides a comprehensive overview of the impact of Mn on vascular endothelium, focusing on both peripheral and brain endothelial cells. In vitro studies have demonstrated that high concentrations of Mn can induce endothelial cell cytotoxicity, increase permeability, and disrupt cell-cell junctions through mechanisms involving oxidative stress, mitochondrial damage, and activation of signaling pathways, such as Smad2/3-Snail. Conversely, low concentrations of Mn may protect endothelial cells from the deleterious effects of high glucose and advanced glycation end-products. In the central nervous system, Mn can cross the blood-brain barrier (BBB) and accumulate in the brain parenchyma, leading to neurotoxicity. Several transport mechanisms, including ZIP8, ZIP14, and SPCA1, have been identified for Mn uptake by brain endothelial cells. Mn exposure can impair BBB integrity by disrupting tight junctions and increasing permeability. In vivo studies have corroborated these findings, highlighting the importance of endothelial barriers in mediating Mn toxicity in the brain and kidneys. Maintaining optimal Mn homeostasis is crucial for preserving endothelial function, and further research is needed to develop targeted therapeutic strategies to prevent or mitigate the adverse effects of Mn overexposure.

Keywords

Acknowledgement

MA was supported in part by a grant from the National Institute of Environmental Health Sciences (NIEHS) R01ES10563. AAT and AVS were supported by the Russian Ministry of Science and Higher Education (FENZ-2023-0004).

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