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 1

Loss of ALK1 signaling induces vascular malformations in the PNVP.

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Loss of ALK1 signaling induces vascular malformations in the PNVP. (A) L...
(A) Left, experimental timeline of tamoxifen administration and tissue analysis in Alk1iECKO and control mice. Right, representative images showing CD31 and α-SMA immunostaining of the PNVP and INVP at P8, indicating vascular morphology. α-SMA, α–smooth muscle actin; PNVP, perineural vascular plexus; INVP, intraneural vascular plexus; l/l, lox/lox. (B) CD31 immunostaining of the PNVP of Alk1iECKO and control mice at P8. (C) Quantification of vascular area in the PNVP of Alk1iECKO and control mice (n = 4 for each condition). (D and E) Quantification of vessel diameter in the PNVP of Alk1iECKO and control mice at P8 (n = 4 for each condition). (F) CD31 immunostaining showing direct AV connections in the PNVP of Alk1iECKO mice. (G) Quantification of PNVP AV shunts in the PNVP of Alk1iECKO and control mice (n = 13 for each condition). (H) Quantification of PNVP AV shunt diameter in the PNVP of Alk1iECKO and control mice at P8 (n = 11 for each condition). (I) CD31 immunostaining of brain sections from Alk1iECKO and control mice at P8. (J and K) Quantification of vascular area (n = 3 for each condition) (J) and vessel diameter (n = 3 for each condition) (K) in the INVP of Alk1iECKO and control mice at P8. Each dot represents 1 mouse. Data represent means ± SEM. *P < 0.05, ***P < 0.001, Mann-Whitney test (C–E, G, H, and K), Welch’s t test (D, E, G, and H), or unpaired t test (E, J, and K) was performed.