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Updated: Sep 7, 2025
Stretch in Brain Microvascular Endothelial Cells cEND as an In Vitro Traumatic Brain Injury Model of the Blood Brain Barrier
Published on: October 26, 2013
Ferroptosis in brain microvascular endothelial cells mediates blood-brain barrier disruption after traumatic brain
Jiang Fang1, Qiang Yuan1, Zhuoying Du1
1Department of Neurosurgery, Huashan Hospital, Fudan University, Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China.
Abstract:
Ferroptosis is a newly recognized form of regulated cell death. Recently, growing evidence has shown that ferroptosis is involved in the pathogenesis of traumatic brain injury (TBI). However, less attention has been paid to its role in brain microvascular endothelial cells (BMVECs) and blood-brain barrier (BBB) damage, the central pathological process in secondary brain injury of TBI. Here, we established a mechanical stretch injury bEnd.3 model and a Controlled Cortical Impact (CCI) mouse model to explore the ferroptosis-related markers in brain endothelial cells after TBI in vitro and in vivo. From the results of RNA-seq analysis, RT-qPCR and immunostaining, glutathione peroxidase 4 (GPX4) downregulation, Cyclooxygenase-2 (COX-2) upregulation, and iron accumulation were observed in brain endothelial cells after TBI both in vitro and in vivo. Furthermore, we utilized Ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, to investigate the protective effects of ferroptosis inhibition on BBB disruption and neurological deficits. From the results of immunostaining, transmission electron microscopy (TEM), and western blotting, we demonstrated that Fer-1 significantly reduced BMVECs death, BBB permeability, and tight junction loss at 3 days after TBI. The neurological tests including grid walking, rotarod test, and wire-hanging test showed that Fer-1 administration exerted neuroprotective effects in the early stage of TBI. Our findings provided evidences for inhibition of BMVECs ferroptosis as a promising therapeutic target against TBI-induced BBB disruption.
Insights
Ferroptosis, a cell death form, drives brain endothelial cell damage after traumatic brain injury (TBI). Inhibiting ferroptosis protects the blood-brain barrier (BBB) and improves neurological function in TBI models.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Ferroptosis is a regulated cell death pathway implicated in traumatic brain injury (TBI) pathogenesis.
- The role of ferroptosis in brain microvascular endothelial cells (BMVECs) and blood-brain barrier (BBB) damage following TBI remains understudied.
- BBB disruption is a critical factor in secondary brain injury after TBI.
Purpose of the Study:
- To investigate ferroptosis markers in brain endothelial cells after TBI.
- To explore the therapeutic potential of inhibiting ferroptosis in TBI-induced BBB damage and neurological deficits.
Main Methods:
- Established in vitro (mechanical stretch injury) and in vivo (Controlled Cortical Impact - CCI) TBI models.
- Analyzed ferroptosis markers (GPX4, COX-2, iron accumulation) using RNA-seq, RT-qPCR, and immunostaining.
- Administered Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, and evaluated its effects on BMVECs, BBB integrity, and neurological function via TEM, Western blotting, and behavioral tests.
Main Results:
- TBI induced GPX4 downregulation, COX-2 upregulation, and iron accumulation in brain endothelial cells.
- Fer-1 treatment significantly reduced BMVEC death, BBB permeability, and tight junction loss post-TBI.
- Fer-1 administration improved neurological outcomes in early-stage TBI, as evidenced by grid walking, rotarod, and wire-hanging tests.
Conclusions:
- Ferroptosis plays a significant role in TBI-induced brain endothelial cell damage and BBB disruption.
- Inhibition of ferroptosis in BMVECs is a promising therapeutic strategy for mitigating TBI-related BBB damage.
- Targeting BMVEC ferroptosis offers a potential therapeutic avenue for managing TBI.
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