NINJ1 hypomethylation enhances endothelial dysfunction in brain arteriovenous malformations

Area of Science:

• Vascular Biology
• Epigenetics
• Neuroscience

Background:

• Brain arteriovenous malformations (bAVMs) cause intracranial hemorrhage in young patients.
• The molecular basis of bAVM endothelial dysfunction and vascular fragility is not fully understood.
• While KRAS-MAPK pathway activation is implicated, the role of epigenetic dysregulation is unclear.

Purpose of the Study:

• To investigate the genome-wide DNA methylation landscape in bAVM tissues.
• To identify novel epigenetic contributors to bAVM pathogenesis.
• To elucidate the functional role of NINJ1 in endothelial dysfunction and vascular integrity.

Main Methods:

• Genome-wide DNA methylation profiling (Illumina MethylationEPIC v2 array).
• Targeted pyrosequencing and immunofluorescence validation.
• Functional studies in human brain microvascular endothelial cells and zebrafish models.

Main Results:

• Distinct epigenetic landscape in bAVM tissue with enriched genes in angiogenesis and signaling.
• Nerve Injury-Induced Protein 1 (NINJ1) identified as hypomethylated and upregulated in bAVMs.
• NINJ1 overexpression enhanced endothelial proliferation, migration, and tube formation, while knockdown reversed these effects.
• NINJ1 enhanced KRAS-MAPK/ERK signaling, increased endothelial permeability, and impaired vascular integrity in vivo.

Conclusions:

• Promoter hypomethylation and NINJ1 activation are novel epigenetic contributors to bAVM endothelial dysfunction.
• NINJ1 acts as an upstream enhancer of KRAS-MAPK signaling, promoting vascular instability.
• Epigenetic dysregulation of NINJ1 may increase hemorrhage risk in bAVMs.