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Nat Commun. 2016 Nov 29;7:13650. doi: 10.1038/ncomms13650.

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

Author information

1
Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
2
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
3
Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
4
Translation Research Laboratory, Catalan Institute of Oncology, Idibell, Barcelona 08908, Spain.
5
Molecular Oncology, Genentech, Inc., South San Francisco, California 94080-4990, USA.
6
Department of Physiology and Functional Genomics, University of Florida College of Medicine, PO Box 100274, Gainesville, Florida 32610, USA.
7
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
8
Inserm U970, Paris Cardiovascular Research Center, Paris 75015, France.

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.

PMID:
27897192
PMCID:
PMC5141347
DOI:
10.1038/ncomms13650
[Indexed for MEDLINE]
Free PMC Article

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