Endothelial Iron Homeostasis Regulates Blood-Brain Barrier Integrity via the HIF2α-Ve-Cadherin Pathway.

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

doi:10.3390/pharmaceutics13030311

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.

Highlights

The blood–brain barrier (BBB) is composed of the capillaries of the central nervous system (CNS) which tightly regulate the movement of molecules, ions, and cells between blood and brain [1,2]
We found that an increase in the brain endothelial cells (BEC) labile iron pool (LIP) was responsible for the blood-brain barrier (BBB) breakdown while DFO abrogated this effect by inhibiting the increase in Labile iron pool (LIP), inducing the expression of Hypoxia induced factor 2α (HIF2α) and reversing the loss of Ve-cadherin expression
Lipid Peroxidation Is Rapidly Induced in a BBB Injury Model

Summary

Introduction

The blood–brain barrier (BBB) is composed of the capillaries of the central nervous system (CNS) which tightly regulate the movement of molecules, ions, and cells between blood and brain [1,2]. BBB breakdown has been reported as an early physiological occurrence in these diseases and in ageing [25,26,27] Even though these closely associated events have been extensively researched, iron’s effect on BBB integrity and the molecular pathways that govern these effects still remain unclear, since the main emphasis in this field has been to understand iron transport through the BBB to the brain [28]. Another hallmark of these neurodegenerative disorders is an excessive amount of reactive oxygen species (ROS), which is viewed as one of the potential common etiologies in these diseases [29,30,31]. Oxidative stress results in cell membrane damage from lipid peroxidation, changes in protein structure and function due to protein degradation, and structural damage to DNA [34]

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