PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.
Roxana OlaAlexandre DubracJinah HanFeng ZhangJennifer S FangBruno LarrivéeMonica LeeAna A UrarteJan R KraehlingGael GenetKaren K HirschiWilliam C SessaFrancesc V CanalsMariona GrauperaMinhong YanLawrence H YoungPaul S OhAnne EichmannPublished in: Nature communications (2016)
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.
Keyphrases
- endothelial cells
- advanced non small cell lung cancer
- protein kinase
- pi k akt
- vascular endothelial growth factor
- mouse model
- signaling pathway
- mesenchymal stem cells
- genome wide
- cell proliferation
- copy number
- magnetic resonance
- epidermal growth factor receptor
- weight gain
- type diabetes
- gene expression
- preterm infants
- cell cycle arrest
- magnetic resonance imaging
- skeletal muscle
- diabetic retinopathy
- binding protein
- bone marrow
- high fat diet induced
- adipose tissue
- contrast enhanced
- postmenopausal women
- soft tissue