CNS resident macrophages enhance dysfunctional angiogenesis and circulating monocytes infiltration in brain...

Area of Science:

• Neuroimmunology
• Vascular Biology
• Genetics

Background:

• Myeloid immune cells, including macrophages, are prevalent in brain arteriovenous malformations (bAVMs).
• The specific roles of central nervous system (CNS) resident macrophages and circulating monocyte-derived macrophages in bAVM pathogenesis remain unclear.
• Genetic mutations in activin-like kinase 1 (ALK1) or endoglin are linked to bAVM development, causing increased inflammation and immune signaling.

Purpose of the Study:

• To investigate the role of CNS resident macrophages in the development and hemorrhage of bAVMs.
• To determine if targeting CNS resident macrophages can mitigate bAVM progression and severity.

Main Methods:

• Utilized a mouse model with focal brain Alk1 deletion to induce bAVMs.
• Administered a colony-stimulating factor 1 receptor inhibitor to transiently deplete CNS resident macrophages.
• Analyzed bAVM phenotype severity, angiogenesis, vascular dysplasia, immune cell infiltration, and endothelial cell (EC) tight junction protein expression.

Main Results:

• Transient depletion of CNS resident macrophages in early-stage bAVMs inhibited angiogenesis and dysplastic vasculature formation.
• Macrophage depletion reduced immune cell infiltration and improved EC tight junction protein expression.
• In established bAVMs, transient macrophage depletion decreased the number of dysplastic vessels and reduced severe hemorrhage.

Conclusions:

• Endothelial cell mutations in causative bAVM genes activate CNS resident macrophages, driving bAVM progression.
• CNS resident macrophages are key contributors to bAVM development and hemorrhage.
• Targeting CNS resident macrophages presents a potential therapeutic strategy to mitigate bAVM severity.