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

Hereditary Hemorrhagic Telangiectasia type 2 (HHT2), caused by mutations in ACVRL1 ( also known as ALK1), is characterized by brain arteriovenous malformations (bAVMs), abnormal artery-vein connections for which treatment options remain limited. Despite evidence of endothelial cell (EC) heterogeneity, its role in bAVM pathogenesis remains poorly defined. Using endothelial-specific inducible Alk1 knockout mice (Alk1iECKO) and regionally resolved single-cell RNA sequencing, we show that loss of ALK1 signaling induces bAVMs predominantly in the perineural vascular plexus (PNVP). This process is driven by the emergence of a KIT+ angiogenic EC population with human AVM-like transcriptional features, including tip-cell markers and activation of PI3K and KRAS signaling pathways. Cross-species analyses and validation in human samples demonstrate that KIT expression is conserved in endothelial cells from both sporadic and HHT2 brain AVMs. Drug repurposing analysis identified KIT as a top actionable target, and we show that Kit is directly repressed by BMP9-ALK1-SMAD4 signaling. Pharmacological inhibition of KIT reduced angiogenic reprogramming and vascular malformations in vivo without affecting normal vasculature. These findings identify a pathogenic angiogenic EC state and position KIT signaling as a therapeutically actionable pathway in brain AVMs.