Deferoxamine reduces endothelial ferroptosis and protects cerebrovascular function after experimental traumatic brain injury.

Cerebrovascular dysfunction resulting from traumatic brain injury (TBI) significantly contributes to poor patient outcomes. Recent studies revealed the involvement of iron metabolism in neuronal survival, yet its effect on vasculature remains unclear. This study aims to explore the impact of endothelial ferroptosis on cerebrovascular function in TBI. A Controlled Cortical Impact (CCI) model was established in mice, resulting in a significant increase in iron-related proteins such as TfR1, FPN1, and FTH, as well as oxidative stress biomarker 4HNE. This was accompanied by a decline in expression of the ferroptosis inhibitor GPX4. Moreover, Perls' staining and nonhemin iron content assay showed iron overload in brain microvascular endothelial cells (BMECs) and the ipsilateral cortex. Immunofluorescence staining revealed more FTH-positive cerebral endothelial cells, consistent with impaired perfusion vessel density and cerebral blood flow. As a specific iron chelator, deferoxamine (DFO) treatment inhibited such ferroptotic proteins expression and the accumulation of lipid-reactive oxygen species following CCI, enhancing glutathione peroxidase (GPx) activity. DFO treatment significantly reduced iron deposition in BMECs and brain tissue, and increased density of the cerebral capillaries as well. Consequently, DFO treatment led to improvements in cerebral blood flow (as measured by laser speckle imaging) and behavioral performance (as measured by the neurological severity scores, rotarod test, and Morris water maze test). Taken together, our results indicated that TBI induces remarkable iron disorder and endothelial ferroptosis, and DFO treatment may help maintain iron homeostasis and protect vascular function. This may provide a novel therapeutic strategy to prevent cerebrovascular dysfunction following TBI.