Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation

Levet, Sandrine; Ciais, Delphine; Merdzhanova, Galina; Mallet, Christine; Zimmers, Teresa A.; Lee, Se Jin; Navarro, Fabrice; Texier, Isabelle; Feige, Jean‐Jacques; Bailly, Sabine; Vittet, Daniel

doi:10.1182/blood-2012-12-472142

Cited by 125 publications

(124 citation statements)

References 33 publications

Supporting

Mentioning

111

Contrasting

Unclassified

Order By: Relevance

“…In addition to their roles in lymphatic development, cardiac development, and postnatal retinal vascularization (8,30,31), we now show that BMP9 and BMP10 are also important for the closure of the DA. This result is in accordance with the high circulating levels of BMP9 and BMP10 in mice around birth (7,8).…”

Section: Discussionmentioning

confidence: 63%

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

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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.T he ductus arteriosus (DA) is a large blood vessel whose obstruction is essential for the transition from fetal to neonatal circulation. It is a fetal arterial shunt connecting the pulmonary artery with the aortic arch. During fetal life, the DA directs deoxygenated blood away from the pulmonary circulation and toward the descending aorta, bypassing the nonventilated fetal lungs. After birth, the DA closes spontaneously within 1-3 h in small rodents or within 24-48 h in human newborns (1, 2). Although an open DA is required for fetal survival, the persistence of a patent DA (PDA) after birth is a major cause of morbidity and mortality, particularly in preterm neonates, leading to severe complications, including pulmonary hypertension, right ventricular dysfunction, postnatal infections, and respiratory failure. The incidence of PDA has been estimated to be one in 500 interm newborns and accounts for the majority of all cases of congenital heart disease in preterm newborns. It is currently believed that DA closure involves a two-step process (3, 4). The first, provisional closure, also called functional closure, occurs at birth and is accomplished by smooth muscle cell contraction and DA constriction. The second step, named anatomical closure, involves a profound remodeling of cells within the former DA lumen and permits permanent closure of the DA. Although several factors have been implicated in DA closure (oxygen tension, prostaglandin E2, laminin, growth ho...

show abstract

Section: Discussionmentioning

confidence: 63%

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

Levet

Ouarné

Ciais

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The role of the BMP signaling pathway during lymphatic formation has also been analyzed in mice. In line with the Bmp2b-associated phenotypes observed in zebrafish, Bmp9 was shown to negatively regulate lymphatic formation in mammals (Levet et al, 2013;Yoshimatsu et al, 2013). Bmp9 KO results in dilation of the dermal lymphatics at E15.5, suggesting enhanced proliferation of LECs (Yoshimatsu et al, 2013).…”

Section: Transcriptional Control Of Lymphatic Cell Fate Specificationmentioning

confidence: 55%

“…Members of the BMP family act as repressors of lymphatic formation in vivo (Dunworth et al, 2014;Levet et al, 2013;Yoshimatsu et al, 2013). In zebrafish, Bmp2b upregulation at 25-26 hpf induces ectopic venous sprouting, whereas forced expression of Noggin 3, which is an endogenous inhibitor of BMP signaling, results in impaired caudal vein plexus formation (Wiley et al, 2011).…”

Section: Transcriptional Control Of Lymphatic Cell Fate Specificationmentioning

confidence: 99%

Development of the lymphatic system: new questions and paradigms

2016

View full text Add to dashboard Cite

The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells.

show abstract

“…With the identification of BMP-9 as a ligand for ALK-1 in ECs, BMP-9-ALK-1 signaling was shown to inhibit EC proliferation and angiogenesis (12), yet was also seen to promote EC proliferation and capillary sprouting (13). In lymphatic development, blockade of ALK-1 signaling in mice results in impaired lymphangiogenesis (14), whereas BMP-9 deficiency causes abnormal lymphatic development and impaired lymphatic draining (15).…”

mentioning

confidence: 99%