Reactive astrocytes promote breakdown of the blood-brain barrier in multiple sclerosis. Chapouly et al. demonstrate that astrocyte-derived VEGF-A and DDR, the enzymatic product of a newly recognised astrocyte-derived protein, endothelial cell growth factor-1/thymidine phosphorylase (ECGF1/TP), synergistically drive blood-brain barrier permeability in inflammatory brain lesions.