Endothelial iron homeostasis regulates blood-brain barrier integrity via the HIF2α—Ve-cadherin pathway

Daniel Rand, Orly Ravid, Dana Atrakchi, Hila Israelov, Yael Bresler, Chen Shemesh, Liora Omesi, Sigal Liraz-Zaltsman, Fabien Gosselet, Taber S. Maskrey, Michal Schnaider Beeri, Peter Wipf, Itzik Cooper*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The objective of this study was to investigate the molecular response to damage at the blood brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have used a human, stem-cell derived in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. Chemical injury induced by exposure to an organophosphate resulted in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability were induced, leading to apoptotic cell death. Yet, these processes did not directly result in damage to barrier functionality, since blocking them did not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreased MRF and apoptosis subsequent to barrier insult, while also rescuing barrier integrity by inhibiting the labile iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin specifically on the endothelial cell surface. Moreover, the novel nitroxide JP4-039 significantly rescued both injury-induced endothelium cell toxicity and barrier functionality. Elucidating a regulatory pathway that maintains BBB integrity illuminates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases.

Original languageAmerican English
Article number311
Pages (from-to)1-24
Number of pages24
JournalPharmaceutics
Volume13
Issue number3
DOIs
StatePublished - 28 Feb 2021

Bibliographical note

Publisher Copyright:
© 2021 by the author. Licensee MDPI, Basel, Switzerland.

Keywords

  • Blood-brain barrier
  • DFO
  • HIF2α
  • Iron
  • Ve-cadherin

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