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

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Abstract

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 EC-specific inducible Alk1-knockout mice (Alk1iECKO) and regionally resolved single-cell RNA sequencing, we showed that loss of ALK1 signaling induces bAVMs predominantly in the perineural vascular plexus. 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 demonstrated that KIT expression is conserved in ECs from both sporadic and HHT2 bAVMs. Drug-repurposing analysis identified KIT as a top actionable target, and we showed 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 bAVMs.

Authors

Elise Drapé, Lauranne Carrier, Gael Cagnone, Atik Rohmana Maftuhatul Fuad, Mathilde Bizou, Damian Sanchez, Typhaine Anquetil, Jack Wang, Halima Drissi Touzani Walali, Adnan Gopinadhan, Patrick Piet van Vliet, Joel P. Howard, Mysha Ibnat, Gregor Andelfinger, Ethan Winkler, Bruno Larrivée, Alexandre Dubrac