Histopathological studies of multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), and its animal model experimental autoimmune encephalomyelitis (EAE) have found newly formed leaky vessels in demyelinated acute and chronic plaques, in addition to blood-brain barrier damage in existing vessels, that exacerbate disease pathology by increasing CNS infiltration of immune cells. However, which vessel subtypes and signaling pathways generate these aberrant vessels is poorly understood. Using single-cell RNA sequencing and in vivo validation, we find that transcriptome signatures of neo-angiogenesis arise in venous endothelial cells in both acute and chronic EAE, and correlate with upregulation in VEGF-A signaling. These neo-angiogenic markers are also increased in human MS lesions. Treatment with a VEGF-A blocking antibody ameliorates EAE pathology by reducing neo-angiogenic transcriptomic signatures in vivo, suggesting that VEGF-A drives angiogenesis from vein ECs in EAE. Our findings suggest novel therapies targeting the vasculature that could benefit chronic MS.