Isolated Pulmonary Arteriovenous Malformations Associated With BMPR2 Pathogenic Variants

Kularatne, Mithum; Eyries, Mélanie; Savale, Laurent; Humbert, Marc; Montani, David

doi:10.1016/j.chest.2023.04.031

Cited by 3 publications

(2 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, loss-of-function mutations in ALK1, ENG, or SMAD4, and more rarely in GDF2, are known causes of hereditary hemorrhagic telangiectasia (HHT)-a rare vascular multisystemic disease that leads to epistaxis, anemia due to blood loss, and arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain 21,22 . Finally, recent reports of isolated pulmonary AVMs associated with BMPR2 pathogenic variants highlight the complex pulmonary vascular consequences of genetic defects in the BMP-ALK1-Smad1/5/8 pathway 23 . Although PAH and HHT share defects of key common members of the BMP-ALK1-Smad1/5/8 pathway, the reasons of their markedly different clinical presentation and penetrance (<30% in PAH and 100% in HHT) are still currently unknown.…”

Section: Discussionmentioning

confidence: 98%

Bone Morphogenetic Protein-9 Controls Pulmonary Vascular Growth and Remodeling

Berrebeh

Mbouamboua

Thuillet

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background?Pulmonary arterial hypertension (PAH), a life-limiting condition characterized by dysfunction of pulmonary microvascular endothelium, is predisposed by mutations in several genes that are critical for the proper activation of specific bone morphogenetic protein (BMP) receptor complexes that phosphorylate intracellular Smad1/5/8 in endothelial cells. However, the functional importance of BMP-9 (GDF2), one of the high affinity ligands for ALK1 (ACVRL1) and BMPR-II (BMPR2), for the pulmonary microvasculature remains imperfectly understood. Objective—The aim of this study was first to determine the in vivo impact of BMP-9 deficiency on pulmonary vascular growth and remodeling, then to assess whether ALK1 expression can alter BMP-9 transcriptional signatures in human pulmonary microvascular endothelial cells (PMECs). Methods—CRISPR-Cas9 gene editing was used to create Gdf2 knockout rats in Sprague Dawley background. Computed micro-tomography (Micro-Ct) scan after Microfil perfusion was performed to generate high-resolution 3D-images of the pulmonary arterial tree. The influence of ALK1 abundance on the transcriptional signatures of BMP-9 responses in human PMECs was assessed by single cell (sc)-RNAseq. Functional studies were performed using human PMECs exposed to BMP-9, the ALK1/2 inhibitor ML347, and ALK1-Fc fusion protein that neutralizes BMP9/10 and two animal models of severe pulmonary hypertension (PH). Results—Micro-Ct angiography revealed structural and functional remodeling along the pulmonary vascular tree in BMP-9 deficient rats, resulting in vasodilation and increase in vascular density. scRNA-seq experiments identified distinct transcriptional signatures in human PMECs in response to BMP-9 responses. ALK1 expression had a direct impact on both proangiogenic capacities and transcriptional responses of PMECs to BMP-9. Functional studies performed in human PMECs confirmed that abundance of BMP-9 and ALK1 acted as modulators of PMEC tube formation, migration and proliferation, and also of vascular endothelial growth factor (VEGF)/VEGFR activities. The structural and functional remodeling observed in Gdf2 knockout rats coincided with a lower susceptibility to develop severe PH induced by monocrotaline (MCT) and SU5416+hypoxia (SuHx). Conclusion—BMP-9 and ALK1 are critical modulators of pulmonary vascular growth and remodeling. Our results provide potential mechanisms explaining why BMP-9 deficient animals are less susceptible to the rise in pulmonary vascular resistance in experimental models of PH.

show abstract

Section: Discussionmentioning

confidence: 98%

Bone Morphogenetic Protein-9 Controls Pulmonary Vascular Growth and Remodeling

Berrebeh

Mbouamboua

Thuillet

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, in those ACVR1L mutant affected HHT2 patients, PAH is seen as an extremely rare complication [228]. Similarly, GDF2 mutations cause a vascular-anomaly syndrome somehow overlapping with HHT [205], and some BMPR2 variants increase the risk of developing pulmonary AVMs reminiscent of an HHT-like condition [229]. Vice versa, it is not surprising that ACVR1L mutations can also cause PAH-like and HHT symptoms [228,230] in the same patient.…”

Section: Hereditary Haemorrhagic Telangiectasia and Hipscsmentioning

confidence: 99%

Human iPSCs as Model Systems for BMP-Related Rare Diseases

Sánchez-Duffhues,

Hiepen

2023

Cells

View full text Add to dashboard Cite

Disturbances in bone morphogenetic protein (BMP) signalling contribute to onset and development of a number of rare genetic diseases, including Fibrodysplasia ossificans progressiva (FOP), Pulmonary arterial hypertension (PAH), and Hereditary haemorrhagic telangiectasia (HHT). After decades of animal research to build a solid foundation in understanding the underlying molecular mechanisms, the progressive implementation of iPSC-based patient-derived models will improve drug development by addressing drug efficacy, specificity, and toxicity in a complex humanized environment. We will review the current state of literature on iPSC-derived model systems in this field, with special emphasis on the access to patient source material and the complications that may come with it. Given the essential role of BMPs during embryonic development and stem cell differentiation, gain- or loss-of-function mutations in the BMP signalling pathway may compromise iPSC generation, maintenance, and differentiation procedures. This review highlights the need for careful optimization of the protocols used. Finally, we will discuss recent developments towards complex in vitro culture models aiming to resemble specific tissue microenvironments with multi-faceted cellular inputs, such as cell mechanics and ECM together with organoids, organ-on-chip, and microfluidic technologies.

show abstract

Pulmonary vascular phenotype identified in patients withGDF2(BMP9) orBMP10variants: an international multicentre study

Grynblat,

Bogaard,

Eyries

et al. 2024

Eur Respir J

View full text Add to dashboard Cite

BackgroundBone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded byGDF2andBMP10, play a pivotal role in pulmonary vascular regulation.GDF2variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype ofGDF2andBMP10carriers remains largely unexplored.MethodsWe report the characteristics and outcomes of PAH patients inGDF2andBMP10carriers from the French and Dutch PH registry. A literature review explored the phenotypic spectrum of these patients.ResultsTwenty-six PAH patients were identified: 20 harbouring heterozygousGDF2variants, 1 homozygousGDF2variant, 4 heterozygousBMP10variants, and one with bothGDF2andBMP10variants. The prevalence ofGDF2andBMP10variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female-to-male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in NYHA functional class III or IV with severe haemodynamic compromise (median pulmonary vascular resistance 9.0 WU, range 3.3–40.6) WU. Haemoptysis was reported in four patients, none met the HHT criteria. Two patients carryingBMP10variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% ofGDF2carriers developed isolated HHT and identified cardiomyopathy and developmental disorders inBMP10carriers.ConclusionsGDF2andBMP10pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases amongGDF2carriers are limited according to literature.BMP10full phenotypic ramifications warrant further investigation.

show abstract

Isolated Pulmonary Arteriovenous Malformations Associated With BMPR2 Pathogenic Variants

Cited by 3 publications

References 18 publications

Bone Morphogenetic Protein-9 Controls Pulmonary Vascular Growth and Remodeling

Bone Morphogenetic Protein-9 Controls Pulmonary Vascular Growth and Remodeling

Human iPSCs as Model Systems for BMP-Related Rare Diseases

Pulmonary vascular phenotype identified in patients withGDF2(BMP9) orBMP10variants: an international multicentre study

Contact Info

Product

Resources

About