Pharmaceutics
(Feb 2021)
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
Affiliations
- Daniel Rand
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Orly Ravid
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Dana Atrakchi
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Hila Israelov
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Yael Bresler
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Chen Shemesh
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Liora Omesi
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Sigal Liraz-Zaltsman
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Fabien Gosselet
- Blood-Brain Barrier Laboratory (LBHE), Artois University, UR 2465, F-62300 Lens, France
- Taber S. Maskrey
- Department of Chemistry and Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Michal Schnaider Beeri
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- Peter Wipf
- Department of Chemistry and Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Itzik Cooper
- The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer 52621, Israel
- DOI
-
https://doi.org/10.3390/pharmaceutics13030311
- Journal volume & issue
-
Vol. 13,
no. 3
p.
311
Abstract
Read online
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.
Keywords
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