Dimethyl fumarate is an inhibitor of pathological angiogenesis

Vascular endothelial growth factor (VEGF), a pro-angiogenic molecule, supports blood vessel growth during wound healing but also drives pathological neovascularization in blinding eye diseases such as neovascular age-related macular degeneration (nAMD). Dimethyl fumarate (DMFu), an FDA-approved drug for multiple sclerosis, has shown promising anti-inflammatory properties in the retinal pigment epithelium, a crucial structure disrupted in nAMD. Here, we extend the therapeutic potential of DMFu by discerning the anti-angiogenic capabilities of DMFu in choroidal and retinal endothelial cells. Choroidal endothelial cell proliferation was significantly attenuated by DMFu in the mouse choroidal sprouting assay. Even in the presence of VEGF, DMFu disrupted cell migration and tube formation in human microvascular retinal endothelial cells (HRECs). Bulk RNA sequencing highlighted that DMFu successfully ameliorated the expression of VEGF-controlled gene expression. Weighted gene co-expression network and gene set enrichment analyses confirmed downregulation of pathways involved in branching blood vessel morphogenesis but also revealed novel transcriptional mechanisms of action, including control of microtubule transport and ATP synthesis coupled electron transport. DMFu induced a decrease in maximal mitochondrial respiration, an increase in glycolysis and glycolytic capacity and reduced Complex II protein expression of the SDHB subunit on western blot. Such metabolic rewiring may limit the bioenergetic demands required to support angiogenic growth. With therapies available for nAMD being both limited and invasive, DMFu is a contender to be rapidly repurposed as an oral, patient-friendly therapeutic alternative.