PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia

Activin receptor-like kinase 1 (ALK1) is an endothelial serine–threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2. Arteriovenous malformations (AVM) is a hallmark of hereditary haemorrhagic telangiectasia type 2, a disease caused by mutations in BMP receptor ALK1. Ola et al . show that AVM can be caused by blocking BMP9 and BMP10 in mice, leading to increased VEGF and PI3K activity, and that pharmacologic inhibition of PI3K prevents AVM development.