Targeting KIT prevents brain arteriovenous malformations driven by ALK1-deficient angiogenic endothelial cells
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
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
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Research Article Cell biology Vascular biology

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

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

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Figure 2

ScRNA-seq reveals distinct EC reprogramming in Alk1iECKO brains.

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ScRNA-seq reveals distinct EC reprogramming in Alk1iECKO brains. (A) UMA...
(A) UMAP plots of EC clusters from INVP and PNVP of Alk1iECKO and control brains obtained by scRNA-seq. (B) Proportion of EC clusters in indicated conditions. (C) Bar plot of VISION score log2FC (Alk1iECKO vs. control) of ALK1 signaling target gene set in PNVP and INVP ECs. (D) Dot plot of the ALK1 signaling target genes’ expression. (E) UMAP plot of EC clusters from INVP and PNVP of Alk1iECKO and control brains highlighting arterial, venular, and venous ECs. (F) Bar plot of VISION score log2FC (Alk1iECKO vs. control) of arterial (top) and venous (bottom) gene set signatures in PNVP and INVP ECs. (G) Double ERG and EdU immunolabeling of P8 Alk1iECKO and control brains. The white dotted line delineates the boundary between the PNVP and the INVP. The white dotted box indicates the region shown at higher magnification below. (H) Quantification of ERG+EdU+/ERG+ cells in PNVP and INVP from Alk1iECKO (n = 5) and control (n = 4) mice. Each dot represents 1 mouse. Data represent means ± SEM. ****P < 0.0001. Ordinary 1-way ANOVA (H) and Wilcoxon’s rank sum test (C and F) were performed.