Dimethyl fumarate is an inhibitor of pathological angiogenesis

Area of Science:

• Ophthalmology
• Molecular Biology
• Drug Repurposing

Background:

• Vascular endothelial growth factor (VEGF) drives pathological neovascularization in blinding eye diseases like neovascular age-related macular degeneration (nAMD).
• Dimethyl fumarate (DMFu), an FDA-approved drug, exhibits anti-inflammatory properties relevant to retinal pigment epithelium damage in nAMD.

Purpose of the Study:

• To investigate the anti-angiogenic effects of Dimethyl fumarate (DMFu) on choroidal and retinal endothelial cells.
• To elucidate the molecular mechanisms underlying DMFu's anti-angiogenic potential in the context of nAMD.

Main Methods:

• Mouse choroidal explant sprouting assay to assess endothelial cell proliferation.
• In vitro assays using human microvascular retinal endothelial cells (HRECs) to evaluate cell migration and tube formation.
• Bulk RNA sequencing, weighted gene co-expression network analysis, and gene set enrichment analysis to identify transcriptional changes.
• Mitochondrial respiration assays and Western blotting to assess metabolic and protein alterations.

Main Results:

• DMFu significantly inhibited choroidal endothelial cell proliferation.
• DMFu disrupted VEGF-induced cell migration and tube formation in HRECs.
• DMFu downregulated genes involved in blood vessel morphogenesis and altered pathways related to microtubule transport and ATP synthesis.
• DMFu decreased mitochondrial respiration and SDHB protein expression, while increasing glycolysis.

Conclusions:

• DMFu demonstrates significant anti-angiogenic properties relevant to nAMD.
• DMFu's mechanism involves modulating endothelial cell metabolism and gene expression.
• DMFu represents a promising candidate for oral therapeutic repurposing in nAMD due to its efficacy and patient-friendly administration.