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

doi:10.3390/pharmaceutics13030311

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 journal › Article › peer-review

22 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 re-sulted 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.

Original language	English
Article number	311
Pages (from-to)	1-24
Number of pages	24
Journal	Pharmaceutics
Volume	13
Issue number	3
DOIs	https://doi.org/10.3390/pharmaceutics13030311
State	Published - Mar 2021

Funding

Funders	Funder number
Aaron Gutwirth Fund
Defense Threat Reduction Agency-Joint Science and Technology Office for Chemical and Biological Defense	11816372
Nehemia Rubin Excellence in Biomedical Research
Ministry of Science and Technology, Israel	3-13576

Keywords

Blood-brain barrier
DFO
HIF2α
Iron
Ve-cadherin

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10.3390/pharmaceutics13030311

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Rand, D., Ravid, O., Atrakchi, D., Israelov, H., Bresler, Y., Shemesh, C., Omesi, L., Liraz-Zaltsman, S., Gosselet, F., Maskrey, T. S., Beeri, M. S., Wipf, P., & Cooper, I. (2021). Endothelial iron homeostasis regulates blood-brain barrier integrity via the HIF2α—Ve-cadherin pathway. Pharmaceutics, 13(3), 1-24. Article 311. https://doi.org/10.3390/pharmaceutics13030311

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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 re-sulted 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.",

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

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