Targeting KIT prevents brain arteriovenous malformations driven by ALK1-deficient angiogenic endothelial cells

Area of Science:

• Vascular Biology
• Genetics
• Oncology

Background:

• Hereditary Hemorrhagic Telangiectasia type 2 (HHT2), linked to ACVRL1/ALK1 mutations, causes brain arteriovenous malformations (bAVMs) with limited treatments.
• Endothelial cell (EC) heterogeneity's role in bAVM pathogenesis is not well understood.

Purpose of the Study:

• To investigate the role of endothelial ALK1 signaling in bAVM development.
• To identify specific EC populations and molecular pathways driving bAVM formation.
• To explore therapeutic targets for bAVMs.

Main Methods:

• Utilized endothelial-specific inducible Alk1 knockout mice (Alk1iECKO).
• Performed single-cell RNA sequencing to analyze ECs in bAVMs.
• Conducted cross-species analyses and validated findings in human samples.
• Performed drug repurposing analysis and in vivo pharmacological inhibition.

Main Results:

• Loss of ALK1 signaling induced bAVMs, primarily in the perineural vascular plexus (PNVP).
• A KIT+ angiogenic EC population with AVM-like transcriptional features emerged.
• KIT expression was conserved in human sporadic and HHT2 bAVMs.
• KIT signaling inhibition reduced bAVMs in vivo without harming normal vasculature.

Conclusions:

• Identified a pathogenic angiogenic EC state driven by ALK1 loss.
• Demonstrated that KIT signaling is a therapeutically actionable pathway for bAVMs.
• Highlighted the importance of EC heterogeneity in bAVM pathogenesis.