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

Roxana Ola, Alexandre Dubrac, Jinah Han, Feng Zhang, Jennifer S. Fang, Bruno Larrivée, Monica Lee, Ana A. Urarte, Jan R. Kraehling, Gael Genet, Karen K. Hirschi, William C. Sessa, Francesc V. Canals, Mariona Graupera, Minhong Yan, Lawrence H. Young, Paul S. Oh and Anne Eichmann ()
Additional contact information
Roxana Ola: Cardiovascular Research Center, Yale University School of Medicine
Alexandre Dubrac: Cardiovascular Research Center, Yale University School of Medicine
Jinah Han: Cardiovascular Research Center, Yale University School of Medicine
Feng Zhang: Cardiovascular Research Center, Yale University School of Medicine
Jennifer S. Fang: Cardiovascular Research Center, Yale University School of Medicine
Bruno Larrivée: Cardiovascular Research Center, Yale University School of Medicine
Monica Lee: Yale University School of Medicine
Ana A. Urarte: Vascular Signalling Laboratory, Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat
Jan R. Kraehling: Yale University School of Medicine
Gael Genet: Cardiovascular Research Center, Yale University School of Medicine
Karen K. Hirschi: Cardiovascular Research Center, Yale University School of Medicine
William C. Sessa: Yale University School of Medicine
Francesc V. Canals: Translation Research Laboratory, Catalan Institute of Oncology, Idibell
Mariona Graupera: Vascular Signalling Laboratory, Institut d’Investigació Biomèdica de Bellvitge, L’Hospitalet de Llobregat
Minhong Yan: Molecular Oncology, Genentech, Inc.
Lawrence H. Young: Cardiovascular Research Center, Yale University School of Medicine
Paul S. Oh: University of Florida College of Medicine
Anne Eichmann: Cardiovascular Research Center, Yale University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13650

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