BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain

Bidart, Marie; Ricard, Nicolas; Levet, Sandrine; Samson, Michel; Mallet, Christine; David, Laurent; Subileau, Mariela; Tillet, Emmanuelle; Feige, Jean‐Jacques; Bailly, Sabine

doi:10.1007/s00018-011-0751-1

Cited by 157 publications

(217 citation statements)

References 41 publications

(67 reference statements)

Supporting

Mentioning

186

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). It will be interesting in the future to measure circulating levels of BMP9 and BMP10 in term and preterm infants to test whether there is also an increase in these two factors around birth, and whether we can correlate the circulating levels of these BMPs with the risk of PDA.…”

Section: Discussionsupporting

confidence: 80%

“…In 2007, it was demonstrated that BMP9 and BMP10 bind with high affinity to the endothelial-specific receptor activin receptor-like kinase 1 (ALK1), a type 1 receptor of the TGFβ family (6) whose mutations are involved in vascular diseases (5). Both BMP9 and BMP10 are present in blood, and their circulating levels are particularly elevated in mice around birth (7,8), suggesting that they could play a role in pre-and postnatal development. In the present work, we addressed whether BMP9 and BMP10 could be involved in DA closure.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

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

“…To better understand such differences among members of the TGF-β family, we examine the structure of pro-BMP9 and compare it to the previously described, cross-armed conformation of pro-TGF-β1 (10). Although a member of the BMP subfamily and possessing chondrogenic and osteogenic activity, BMP9 is expressed in liver and is required for properly organized blood and lymphatic vascular development (11,12). Mutations in the prodomain of BMP9, in its receptor Alk1, and in its coreceptor endoglin cause phenotypically overlapping hereditary hemorrhagic telangiectasias (13)(14)(15).…”

mentioning

confidence: 99%

Structure of bone morphogenetic protein 9 procomplex

Brown

Gao

et al. 2015

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

106

219

View full text Add to dashboard Cite

Bone morphogenetic proteins (BMPs) belong to the TGF-β family, whose 33 members regulate multiple aspects of morphogenesis. TGF-β family members are secreted as procomplexes containing a small growth factor dimer associated with two larger prodomains. As isolated procomplexes, some members are latent, whereas most are active; what determines these differences is unknown. Here, studies on pro-BMP structures and binding to receptors lead to insights into mechanisms that regulate latency in the TGF-β family and into the functions of their highly divergent prodomains. The observed open-armed, nonlatent conformation of pro-BMP9 and pro-BMP7 contrasts with the cross-armed, latent conformation of pro-TGF-β1. Despite markedly different arm orientations in pro-BMP and pro-TGF-β, the arm domain of the prodomain can similarly associate with the growth factor, whereas prodomain elements N-and C-terminal to the arm associate differently with the growth factor and may compete with one another to regulate latency and stepwise displacement by type I and II receptors. Sequence conservation suggests that pro-BMP9 can adopt both crossarmed and open-armed conformations. We propose that interactors in the matrix stabilize a cross-armed pro-BMP conformation and regulate transition between cross-armed, latent and open-armed, nonlatent pro-BMP conformations.

show abstract

“…We anticipate occurrence of these and also interactions between BMP9 and the GH-STAT5 axis in pulmonary vascular cells (see comments on BMP9 in previous section and refs. [79][80][81][82][83][84].…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

View full text Add to dashboard Cite

Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

show abstract

BMP9 is produced by hepatocytes and circulates mainly in an active mature form complexed to its prodomain

Cited by 157 publications

References 41 publications

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

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

Structure of bone morphogenetic protein 9 procomplex

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Contact Info

Product

Resources

About