Blood-Brain Barrier Dysfunction in Cerebral Arteriovenous Malformations. A Murine Model of Hypoperfusion-Reperfusion Injury Assessed with Dynamic Contrast-Enhanced MRI

Background The presence of an arteriovenous malformation in the brain (bAVM) induces hemodynamic changes, namely chronic hypoperfusion, loss of autoregulation and venous congestion, leading to proinflammatory states and blood-brain barrier (BBB) dysfunction. Conversely, bAVM treatment is thought to modify this longstanding hemodynamic condition abruptly, potentially leading to adverse responses in the surrounding brain. We designed and validated a murine model that mimics the hypoperfusion-reperfusion effect of bAVM and assessed BBB changes with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods Cerebral hypoperfusion and venous congestion were induced in rats by bilateral external carotid artery ligation and unilateral jugular-carotid anastomosis. 21 days were allowed for chronic adaptative changes, then the fistula was closed by jugular ligation for reperfusion. Neurological examination and MRI were performed at 1, 7, and 21 days of evolution and 24 hours after ligation. Confirmation of DCE findings was performed ex-vivo with IgG immunofluorescence. Results MRI observations confirmed that the model successfully replicates arterial hypoperfusion and venous hypertension without signs of malignant oedema or ischemia. Neurofunctional assessment showed a progressive neurological decline with a tendency to improvement after shunt ligation. DCE-MRI showed progressive BBB disruption and restoration after ligation, objectively quantified by increases in Ktrans values. Similar results were obtained by immunofluorescence analysis. Conclusion We present a well-founded murine model of brain hemodynamic changes observed before and after surgical treatment of bAVMs. These findings may provide novel insight into bAVM physiopathology, changes induced in the surrounding brain, mechanisms underlying symptoms, and brain adaptative responses after surgical treatment.