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

Sandrine Levet; Marie Ouarné; Delphine Ciais; Charles Coutton; Mariela Subileau; Christine Mallet; Nicolas Ricard; Marie Bidart; Thierry Debillon; Francesca Faravelli; Caroline Rooryck; Jean-Jacques Feige; Emmanuelle Tillet; Sabine Bailly

doi:10.1073/pnas.1508386112

New Research In

Edited by Napoleone Ferrara, University of California, San Diego, La Jolla, CA, and approved May 19, 2015 (received for review April 30, 2015)

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.

Footnotes

↵¹S.L. and M.O. contributed equally to this work.
↵²E.T. and S.B. contributed equally to this work.
↵³To whom correspondence should be addressed. Email: sabine.bailly{at}cea.fr.

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.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1508386112/-/DCSupplemental.