Background and purpose: Accumulation of macrophages and microglia is evidenced in the lesions of human and mouse brain arteriovenous malformations (bAVMs) with or without hemorrhage, suggesting that these cells play an active role in bAVM pathogenesis. We hypothesize that transient depletion of microglia reduces bAVM severity.
Methods: Brain AVM was induced in adult mice that have activin-like kinase 1 (Alk1, an AVM causative gene) gene exons 4-6 floxed by co-injection of an adenoviral vectors expressing Cre-recombinase and an adeno-associated viral vectors expressing vascular endothelial growth factor into the basal ganglia. Brain microglia were depleted transiently by administration of an inhibitor of colony stimulating factor receptor (CSF1R inhibitor, 180 mg/kg/day of body weight) through chow for 7 days starting 1- (when angiogenesis occurred) or 8-weeks (when bAVMs had formed) after model induction. Brain AVM severity was analyzed through quantification of abnormal vessels, macrophage/microglia and hemorrhage (Prussian blue staining) in the lesion (n=6).
Results: Administration of CSF1R inhibitor to wild-type mice for 7 days depleted 93% of microglia in their brains. CSF1R inhibitor treatment starting at 1-week after model induction inhibited bAVM formation. There were less abnormal vessels in the treated group (14±0.9 vessels/mm2) compared to that in the control group (23±0.9 vessels/mm2, P=0.001) at 8 weeks after model induction. Administration of CSF1R inhibitor starting 8-weeks after the model induction when bAVMs were fully formed also reduced the number of abnormal vessels (control: 25±1.4 vessels/mm2 vs. treated: 14.±0.8 vessels/mm2, P<0.001) analyzed at 9-weeks after model induction when the treatment stopped. CSF1R inhibitor treatment has also reduced the number of microglia in bAVM lesion (P=0.03 for 1-week-group and P=0.003 for 8-week-group), which was correlated with the reduction of abnormal vessels (R2=0.63, P=0.0001) and hemorrhage.
Conclusion: Transient depletion of microglia could be developed into a new therapy for reduction of bAVM severity.