title: PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia.
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.
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Roxana
authors.initials: R
authors.lastname: Ola
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dubrac
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Jinah
authors.initials: J
authors.lastname: Han
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Fang
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Larrivée
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Lee
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Urarte
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jan R
authors.identifier: 0000-0002-0979-2900
authors.initials: JR
authors.lastname: Kraehling
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Gael
authors.initials: G
authors.lastname: Genet
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Hirschi
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.affiliation: Translation Research Laboratory, Catalan Institute of Oncology, Idibell, Barcelona 08908, Spain.
authors.forename: Francesc V
authors.initials: FV
authors.lastname: Canals
authors.affiliation: Vascular Signalling Laboratory, Institut d'Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Graupera
authors.affiliation: Molecular Oncology, Genentech, Inc., South San Francisco, California 94080-4990, USA.
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Young
authors.affiliation: Department of Physiology and Functional Genomics, University of Florida College of Medicine, PO Box 100274, Gainesville, Florida 32610, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Oh
authors.affiliation: Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.|Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.|Inserm U970, Paris Cardiovascular Research Center, Paris 75015, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D030301:Activin Receptors, Type II; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012160:Retina / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D054079:Vascular Malformations / Q000150:complications* / Q000201:enzymology*
chemical_list: D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D019485:Bone Morphogenetic Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2; C498931:Acvrl1 protein, mouse