BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus

Edited by Napoleone Ferrara, University of California, San Diego, La Jolla, CA, and approved May 19, 2015 (received for review April 30, 2015)
June 8, 2015
112 (25) E3207-E3215

Significance

At birth, newborns must switch from the fetal aquatic life to the aerial one, by closure of a vessel named the ductus arteriosus. During fetal life, it allows blood to bypass the lungs, and a failure of its closure at birth is a major cause of mortality, particularly in preterm neonates. This pathological condition is known as patent ductus arteriosus and occurs in approximately 60% of preterm infants born before 28 wk of gestation. Herein, we show, for the first time to our knowledge, the involvement of two circulating growth factors, bone morphogenetic proteins BMP9 and BMP10, in the anatomical closure of this vessel. This finding will have potential clinical applications in the management of this pathology.

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.

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Acknowledgments

We thank the animal unit staff at Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV) for animal husbandry, Dr. S. J. Lee (Johns Hopkins University School of Medicine) and Dr. T. Zimmers (Thomas Jefferson University) for providing the Bmp9−/− mice, and Dr. O. Filhol and M. Prioux for sharing some PCR primers. This work was supported by INSERM (U1036), CEA, Université Joseph Fourier (UJF), Association pour la Recherche sur le Cancer Grant SFI20111203720, the Groupement d’Entreprises Françaises de Lutte Contre le Cancer (GEFLUC) Dauphiné-Savoie, the Ligue Contre le Cancer de la Loire et de la Savoie, Association Maladie de Rendu-Osler (AMRO), and a Fondation Lefoulon-Delalande postdoctoral grant (to D.C.).

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 112 | No. 25
June 23, 2015
PubMed: 26056270

Classifications

Submission history

Published online: June 8, 2015
Published in issue: June 23, 2015

Keywords

  1. ductus arteriosus
  2. BMP9
  3. BMP10
  4. endMT
  5. pediatric

Acknowledgments

We thank the animal unit staff at Institut de Recherches en Technologies et Sciences pour le Vivant (iRTSV) for animal husbandry, Dr. S. J. Lee (Johns Hopkins University School of Medicine) and Dr. T. Zimmers (Thomas Jefferson University) for providing the Bmp9−/− mice, and Dr. O. Filhol and M. Prioux for sharing some PCR primers. This work was supported by INSERM (U1036), CEA, Université Joseph Fourier (UJF), Association pour la Recherche sur le Cancer Grant SFI20111203720, the Groupement d’Entreprises Françaises de Lutte Contre le Cancer (GEFLUC) Dauphiné-Savoie, the Ligue Contre le Cancer de la Loire et de la Savoie, Association Maladie de Rendu-Osler (AMRO), and a Fondation Lefoulon-Delalande postdoctoral grant (to D.C.).

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Sandrine Levet1
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;
Marie Ouarné1
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;
Delphine Ciais
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;
Charles Coutton
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;
Mariela Subileau
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;
Christine Mallet
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;
Nicolas Ricard
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;
Marie Bidart
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;
Thierry Debillon
Service de Médecine et Réanimation Néonatale, Centre Hospitalier Universitaire de Grenoble, Grenoble, France F-38000;
Francesca Faravelli
Division of Medical Genetics, Galliera Hospital, Genoa, Italy;
Caroline Rooryck
Service de Génétique Médicale, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France F-33000
Jean-Jacques Feige
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;
Emmanuelle Tillet2
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 Bailly3,2 [email protected]
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;

Notes

3
To whom correspondence should be addressed. Email: [email protected].
Author contributions: S.L., M.O., D.C., J.-J.F., E.T., and S.B. designed research; S.L., M.O., D.C., M.S., C.M., N.R., M.B., E.T., and S.B. performed research; C.C., F.F., and C.R. contributed new reagents/analytic tools; S.L., M.O., D.C., C.C., T.D., E.T., and S.B. analyzed data; and S.L., M.O., J.-J.F., E.T., and S.B. wrote the paper.
1
S.L. and M.O. contributed equally to this work.
2
E.T. and S.B. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus
    Proceedings of the National Academy of Sciences
    • Vol. 112
    • No. 25
    • pp. 7617-E3313

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