title: BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus.
abstract: The transition to pulmonary respiration after birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. Two members of the TGFβ family, bone morphogenetic protein 9 (BMP9) and BMP10, have been recently involved in postnatal angiogenesis, both being necessary for remodeling of newly formed microvascular beds. The aim of the present work was to study whether BMP9 and BMP10 could be involved in closure of the DA. We found that Bmp9 knockout in mice led to an imperfect closure of the DA. Further, addition of a neutralizing anti-BMP10 antibody at postnatal day 1 (P1) and P3 in these pups exacerbated the remodeling defect and led to a reopening of the DA at P4. Transmission electron microscopy images and immunofluorescence stainings suggested that this effect could be due to a defect in intimal cell differentiation from endothelial to mesenchymal cells, associated with a lack of extracellular matrix deposition within the center of the DA. This result was supported by the identification of the regulation by BMP9 and BMP10 of several genes known to be involved in this process. The involvement of these BMPs was further supported by human genomic data because we could define a critical region in chromosome 2 encoding eight genes including BMP10 that correlated with the presence of a patent DA. Together, these data establish roles for BMP9 and BMP10 in DA closure.
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Levet
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Marie
authors.initials: M
authors.lastname: Ouarné
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Delphine
authors.initials: D
authors.lastname: Ciais
authors.affiliation: Université Grenoble-Alpes, Grenoble, France F-38000; Laboratoire de Génétique Chromosomique, Département de Génétique et Procréation, Hôpital Couple Enfant, Centre Hospitalier Universitaire de Grenoble, Grenoble F-38000, France; Equipe "Génétique, Infertilité et Thérapeutique," Laboratoire Andrologie Gérontechnologie Inflammation Modélisation, CNRS FRE3405, Grenoble, France F-38000;
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Mariela
authors.initials: M
authors.lastname: Subileau
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Christine
authors.initials: C
authors.lastname: Mallet
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ricard
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Marie
authors.initials: M
authors.lastname: Bidart
authors.affiliation: Service de Médecine et Réanimation Néonatale, Centre Hospitalier Universitaire de Grenoble, Grenoble, France F-38000;
authors.forename: Thierry
authors.initials: T
authors.lastname: Debillon
authors.affiliation: Division of Medical Genetics, Galliera Hospital, Genoa, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Faravelli
authors.affiliation: Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France F-33000.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rooryck
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Feige
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000;
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tillet
authors.affiliation: Institut National de la santé et de la Recherche Médicale (INSERM, U1036), Grenoble, France F-38000; Commissariat à l'Énergie Atomique et aux Energies Alternatives, Institut de Recherches en Technologies et Sciences pour le Vivant, Laboratoire Biologie du Cancer et de l'Infection, Grenoble, France F-38000; Université Grenoble-Alpes, Grenoble, France F-38000; sabine.bailly@cea.fr.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bailly
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology*; D004373:Ductus Arteriosus / Q000473:pathology / Q000502:physiology*; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2
keywords: BMP10; BMP9; ductus arteriosus; endMT; pediatric