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

R Ola, A Dubrac, J Han, F Zhang, JS Fang… - Nature …, 2016 - nature.com
Nature communications, 2016nature.com
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 …
Abstract
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.
nature.com
以上显示的是最相近的搜索结果。 查看全部搜索结果