Cell Signal. 2025 Sep 2:112106. doi: 10.1016/j.cellsig.2025.112106. Online ahead of print.
ABSTRACT
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 previously shown promising anti-inflammatory properties in retinal pigment epithelium, a crucial structure disrupted by nAMD. Here, we extend the multi-phenotypic 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 explant 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. A concordant decrease in maximal mitochondrial respiration and an increase in glycolysis and glycolytic capacity was measured. Complex II protein expression of the SDHB subunit decreased on western blot. 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.
PMID:40907629 | DOI:10.1016/j.cellsig.2025.112106