VEGF-A-mediated venous endothelial cell proliferation results in neoangiogenesis during neuroinflammation

Abstract

Newly formed leaky vessels and blood–brain barrier (BBB) damage are present in demyelinating acute and chronic lesions in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). However, the endothelial cell subtypes and signaling pathways contributing to these leaky neovessels are unclear. Here, using single-cell transcriptional profiling and in vivo validation studies, we show that venous endothelial cells express neoangiogenesis gene signatures and show increased proliferation resulting in enlarged veins and higher venous coverage in acute and chronic EAE lesions in female adult mice. These changes correlate with the upregulation of vascular endothelial growth factor A (VEGF-A) signaling. We also confirmed increased expression of neoangiogenic markers in acute and chronic human MS lesions. Treatment with a VEGF-A blocking antibody diminishes the neoangiogenic transcriptomic signatures and vascular proliferation in female adult mice with EAE, but it does not restore BBB function or ameliorate EAE pathology. Our data demonstrate that venous endothelial cells contribute to neoangiogenesis in demyelinating neuroinflammatory conditions. Defective neoangiogenesis and blood–brain barrier leakiness are pathological hallmarks of neuroinflammation. Here the authors show that vascular endothelial growth factor A (VEGF-A) promotes venous endothelial cell proliferation, resulting in the formation of leaky vessels around demyelinating lesions in multiple sclerosis and experimental autoimmune encephalomyelitis.