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

Grynblat, Julien; Bogaard, Harm Jan; Eyries, Mélanie; Meyrignac, Olivier; Savale, Laurent; Jaïs, Xavier; Ghigna, Maria-Rosa; Celant, Lucas; Meijboom, Lilian; Houweling, Arjan C.; Levy, Marilyne; Antigny, Fabrice; Chaouat, Ari; Cottin, Vincent; Guignabert, Christophe; Coulet, Florence; Sitbon, Olivier; Bonnet, Damien; Humbert, Marc; Montani, David

doi:10.1183/13993003.01634-2023

Cited by 4 publications

(1 citation statement)

References 45 publications

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“…Moreover, dysregulated pulmonary expression of genes associated with pathways known to be dysregulated in PAH, that is, the endothelin ( Edn1 , Edn2 ), prostacyclin ( Gnb4 , Gnb5 , and Gng10 ), and BMP pathways ( Gdf2 ) underscores the pathophysiological and preclinical significance of this innovative rat model of PH. 48 , 49 …”

Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation

Todesco,

Grynblat,

Akoumia

et al. 2024

JAHA

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Background The primary genetic risk factor for heritable pulmonary arterial hypertension is the presence of monoallelic mutations in the BMPR2 gene. The incomplete penetrance of BMPR2 mutations implies that additional triggers are necessary for pulmonary arterial hypertension occurrence. Pulmonary artery stenosis directly raises pulmonary artery pressure, and the redirection of blood flow to unobstructed arteries leads to endothelial dysfunction and vascular remodeling. We hypothesized that right pulmonary artery occlusion (RPAO) triggers pulmonary hypertension (PH) in rats with Bmpr2 mutations. Methods and Results Male and female rats with a 71 bp monoallelic deletion in exon 1 of Bmpr2 and their wild‐type siblings underwent acute and chronic RPAO. They were subjected to full high‐fidelity hemodynamic characterization. We also examined how chronic RPAO can mimic the pulmonary gene expression pattern associated with installed PH in unobstructed territories. RPAO induced precapillary PH in male and female rats, both acutely and chronically. Bmpr2 mutant and male rats manifested more severe PH compared with their counterparts. Although wild‐type rats adapted to RPAO, Bmpr2 mutant rats experienced heightened mortality. RPAO induced a decline in cardiac contractility index, particularly pronounced in male Bmpr2 rats. Chronic RPAO resulted in elevated pulmonary IL‐6 (interleukin‐6) expression and decreased Gdf2 expression (corrected P value<0.05 and log2 fold change>1). In this context, male rats expressed higher pulmonary levels of endothelin‐1 and IL‐6 than females. Conclusions Our novel 2‐hit rat model presents a promising avenue to explore the adaptation of the right ventricle and pulmonary vasculature to PH, shedding light on pertinent sex‐ and gene‐related effects.

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Section: Discussionmentioning

confidence: 99%

Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation

Todesco,

Grynblat,

Akoumia

et al. 2024

JAHA

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Bone morphogenetic protein signalling in pulmonary arterial hypertension: revisiting the BMPRII connection

Li,

Quigley

2024

Biochemical Society Transactions

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Pulmonary arterial hypertension (PAH) is a rare and life-threatening vascular disorder, characterised by abnormal remodelling of the pulmonary vessels and elevated pulmonary artery pressure, leading to right ventricular hypertrophy and right-sided heart failure. The importance of bone morphogenetic protein (BMP) signalling in the pathogenesis of PAH is demonstrated by human genetic studies. Many PAH risk genes are involved in the BMP signalling pathway and are highly expressed or preferentially act on vascular endothelial cells. Endothelial dysfunction is recognised as an initial trigger for PAH, and endothelial BMP signalling plays a crucial role in the maintenance of endothelial integrity. BMPR2 is the most prevalent PAH gene, found in over 80% of heritable cases. As BMPRII protein is the major type II receptor for a large family of BMP ligands and expressed ubiquitously in many tissues, dysregulated BMP signalling in other cells may also contribute to PAH pathobiology. Sotatercept, which contains the extracellular domain of another transforming growth factor-β family type II receptor ActRIIA fused to immunoglobin Fc domain, was recently approved by the FDA as a treatment for PAH. Neither its target cells nor its mechanism of action is fully understood. This review will revisit BMPRII function and its extracellular regulation, summarise how dysregulated BMP signalling in endothelial cells and smooth muscle cells may contribute to PAH pathogenesis, and discuss how novel therapeutics targeting the extracellular regulation of BMP signalling, such as BMP9 and Sotatercept, can be related to restoring BMPRII function.

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Pathology and pathobiology of pulmonary hypertension: current insights and future directions

Guignabert,

Aman,

Bonnet

et al. 2024

Eur Respir J

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In recent years, major advances have been made in the understanding of the cellular and molecular mechanisms driving pulmonary vascular remodelling in various forms of pulmonary hypertension, including pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic lung disease and hypoxia, and chronic thromboembolic pulmonary hypertension. However, the survival rates for these different forms of pulmonary hypertension remain unsatisfactory, underscoring the crucial need to more effectively translate innovative scientific knowledge into healthcare interventions. In these proceedings of the 7th World Symposium on Pulmonary Hypertension, we delve into recent developments in the field of pathology and pathophysiology, prioritising them while questioning their relevance to different subsets of pulmonary hypertension. In addition, we explore how the latest omics and other technological advances can help us better and more rapidly understand the myriad basic mechanisms contributing to the initiation and progression of pulmonary vascular remodelling. Finally, we discuss strategies aimed at improving patient care, optimising drug development, and providing essential support to advance research in this field.

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

Cited by 4 publications

References 45 publications

Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation

Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation

Bone morphogenetic protein signalling in pulmonary arterial hypertension: revisiting the BMPRII connection

Pathology and pathobiology of pulmonary hypertension: current insights and future directions

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