BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension.
The impact of bone morphogenetic protein receptor 2 (BMPR2) gene mutations on vascular remodelling in pulmonary arterial hypertension (PAH) is unknown. We sought to identify a histological profile of BMPR2 mutation carriers.Clinical data and lung histology from 44 PAH patients were subjected to systematic analysis and morphometry.Bronchial artery hypertrophy/dilatation and bronchial angiogenesis, as well as muscular remodelling of septal veins were significantly increased in PAH lungs carrying BMPR2 mutations. We found that patients displaying increased bronchial artery remodelling and bronchial microvessel density, irrespective of the mutation status, were more likely to suffer from severe haemoptysis. History of substantial haemoptysis (>50 mL) was significantly more frequent in BMPR2 mutation carriers. 43.5% of BMPR2 mutation carriers, as opposed to 9.5% of noncarriers, displayed singular large fibrovascular lesions, which appear to be closely related to the systemic lung vasculature.Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Dept of Pathology, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Maria-Rosa
MR
Ghigna
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
Christophe
0000-0002-8545-4452
C
Guignabert
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
David
D
Montani
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Barbara
B
Girerd
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Xavier
X
Jaïs
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Laurent
L
Savale
Dept of Thoracic and Vascular Surgery, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Philippe
P
Hervé
Dept of Pathology, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Vincent
V
Thomas de Montpréville
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Dept of Thoracic and Vascular Surgery, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Olaf
O
Mercier
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Olivier
O
Sitbon
AP-HP, Dept of Genetics, Pitié-Salpétrière Hospital, Université Pierre et Marie Curie, Paris, France.
Florent
F
Soubrier
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Dept of Thoracic and Vascular Surgery, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Elie
E
Fadel
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Gérald
G
Simonneau
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|AP-HP, Dept of Pulmonology, DHU Thorax Innovation, Bicêtre Hospital, Kremlin-Bicêtre, France.
Marc
M
Humbert
INSERM UMR_S 999, LabEx LERMIT, Marie Lannelongue Hospital, Le Plessis-Robinson, France peter.dorfmuller@u-psud.fr.|School of Medicine, Paris South University, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Dept of Pathology, Marie Lannelongue Hospital, Le Plessis-Robinson, France.
Peter
P
Dorfmüller
D000293:Adolescent; D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D001981:Bronchial Arteries / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D065627:Familial Primary Pulmonary Hypertension / Q000235:genetics* / Q000601:surgery; D005260:Female; D005602:France; D006469:Hemoptysis / Q000209:etiology; D006579:Heterozygote; D006801:Humans; D008168:Lung / Q000473:pathology*; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D066253:Vascular Remodeling / Q000235:genetics*; D055815:Young Adult
C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II