BMP signaling in vascular biology and dysfunction

Vinuesa, Amaya García de; Abdelilah‐Seyfried, Salim; Knaus, Petra; Zwijsen, An; Bailly, Sabine

doi:10.1016/j.cytogfr.2015.12.005

Cited by 143 publications

(147 citation statements)

References 188 publications

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Section: Overview Of the Endothelial Bmp Signalling Pathwaymentioning

confidence: 99%

“…The pathway is tightly regulated at multiple levels. The interplay between endothelial BMP signalling with VEGF, Notch, WNT and Hippo pathways confers endothelial cell (EC) identity and heterogeneity, and has been reviewed recently [1].BMP9 and BMP10 are cysteine-knot homodimeric growth factors. They are the major BMP ligands acting on ECs [2], which initiate the signalling cascade by forming a complex with two copies of type I receptor activin receptor-like kinase 1 (ALK1) and two copies of the type II receptor, including BMP receptor type II (BMPR-II), activin receptor type IIa and/or IIb.…”

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confidence: 99%

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Regulation of the ALK1 ligands, BMP9 and BMP10

Salmon

Jiang

et al. 2016

Biochemical Society Transactions

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Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). Administration of recombinant BMP9 reverses experimental PAH in preclinical rodent models. Dalantercept, an Fc-fusion protein of the extracellular domain of ALK1 and a ligand trap for BMP9 and BMP10, is in phase II clinical trials for anti-tumour angiogenesis. Understanding the regulation of BMP9 and BMP10, at both gene and protein levels, under physiological and pathological conditions, will reveal essential information and potential novel prognostic markers for the BMP9/BMP10-targeted therapies.

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Section: Overview Of the Endothelial Bmp Signalling Pathwaymentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of the ALK1 ligands, BMP9 and BMP10

Salmon

Jiang

et al. 2016

Biochemical Society Transactions

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“…Using MO-mediated KD, this study showed that downregulation of the BMP type II receptors Bmpr2a and Bmpr2b, the type I receptors Alk3 (Bmpr1aa) and Alk3b (Bmpr1ab), and Smad5 -an essential cellular mediator of BMP signaling -leads to diverse lymphatic defects . It remains to be elucidated whether additional ligands from the BMP family (de Vinuesa et al, 2016) are capable of eliciting pro-lymphangiogenic responses through binding of these receptors. The role of the BMP signaling pathway during lymphatic formation has also been analyzed in mice.…”

Section: Transcriptional Control Of Lymphatic Cell Fate Specificationmentioning

confidence: 99%

Development of the lymphatic system: new questions and paradigms

2016

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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.

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“…However, recent evidence strongly suggests that the disease is caused by abnormal activation of angiogenesis, a process causing excessive EC proliferation and hypervascularization, which ultimately leads to the development of AVMs21. Indeed, ALK1 and endoglin are predominantly expressed in ECs and BMP9/10 signaling is required for proper vascular development and maintenance, as well as for controlling transcriptional responses critically involved in angiogenesis, such as Notch and Wnt signaling pathways22232425.…”

mentioning

confidence: 99%

A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

Ruíz

Zhao

Chandakkar

et al. 2016

Sci Rep

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Hereditary hemorrhagic telangiectasia (HHT) is a potentially life-threatening genetic vascular disorder caused by loss-of-function mutations in the genes encoding activin receptor-like kinase 1 (ALK1), endoglin, Smad4, and bone morphogenetic protein 9 (BMP9). Injections of mouse neonates with BMP9/10 blocking antibodies lead to HHT-like vascular defects in the postnatal retinal angiogenesis model. Mothers and their newborns share the same immunity through the transfer of maternal antibodies during lactation. Here, we investigated whether the transmammary delivery route could improve the ease and consistency of administering anti-BMP9/10 antibodies in the postnatal retinal angiogenesis model. We found that anti-BMP9/10 antibodies, when intraperitoneally injected into lactating dams, are efficiently transferred into the blood circulation of lactationally-exposed neonatal pups. Strikingly, pups receiving anti-BMP9/10 antibodies via lactation displayed consistent and robust vascular pathology in the retina, which included hypervascularization and defects in arteriovenous specification, as well as the presence of multiple and massive arteriovenous malformations. Furthermore, RNA-Seq analyses of neonatal retinas identified an increase in the key pro-angiogenic factor, angiopoietin-2, as the most significant change in gene expression triggered by the transmammary delivery of anti-BMP9/10 antibodies. Transmammary-delivered BMP9/10 immunoblocking in the mouse neonatal retina is therefore a practical, noninvasive, reliable, and robust model of HHT vascular pathology.

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BMP signaling in vascular biology and dysfunction

Cited by 143 publications

References 188 publications

Regulation of the ALK1 ligands, BMP9 and BMP10

Regulation of the ALK1 ligands, BMP9 and BMP10

Development of the lymphatic system: new questions and paradigms

A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

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