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Published on: March 1, 2022
Pulmonary vascular remodeling patterns and expression of general control nonderepressible 2 (GCN2) in pulmonary
Esther J Nossent1, Fabrice Antigny2, David Montani3
1Department of Pulmonary Diseases, Vrije Universiteit University Medical Center, Institute for Cardiovascular Research, Amsterdam, The Netherlands; Institut National de la Santé et de la Recherche Unités Mixtes de Recherche_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, Paris, France.
Background:
Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD.
Methods:
Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models.
Results:
PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models).
Conclusions:
Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities.
Insights
Heritable pulmonary veno-occlusive disease (PVOD) involves EIF2AK4 gene mutations and GCN2 loss. Decreased GCN2 expression is a shared feature in PVOD and pulmonary arterial hypertension (PAH), suggesting they are part of a disease spectrum.
Area of Science:
- Pulmonary vascular diseases
- Genetics and molecular biology
- Histopathology
Background:
- Heritable pulmonary veno-occlusive disease (PVOD) is associated with mutations in the EIF2AK4 gene, impacting general control nonderepressible 2 (GCN2) function.
- The precise role of GCN2 expression in pulmonary vascular remodeling, a key feature of PVOD, is not fully understood.
- This study aimed to delineate the specific histologic and biologic characteristics of heritable PVOD.
Purpose of the Study:
- To investigate the distinct histologic features differentiating EIF2AK4 mutation carriers from non-carriers in heritable PVOD.
- To quantify and compare GCN2 expression levels in patients with PVOD, pulmonary arterial hypertension (PAH), and experimental models.
- To explore potential shared pathobiologic mechanisms between PVOD and PAH.
Main Methods:
- Systematic histologic analysis and semiautomated morphometry were performed on lung tissue from 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers).
- GCN2 expression was quantified using Western blotting in PVOD patients, PAH patients (BMPR2 mutation carriers and non-carriers), and three experimental pulmonary hypertension models.
- Clinical data and lung histology were analyzed to identify specific morphologic and molecular differences.
Main Results:
- PVOD patients exhibited significantly reduced pulmonary arterial patency compared to healthy controls.
- EIF2AK4 mutation carriers showed distinct arterial remodeling, characterized by more severe intimal fibrosis and less medial hypertrophy, along with increased muscular hyperplasia of interlobular septal veins.
- GCN2 expression was abolished in heritable PVOD and significantly decreased in sporadic PVOD and various forms of PAH, as well as in experimental pulmonary hypertension models.
Conclusions:
- Pulmonary arterial remodeling is a significant feature of PVOD.
- A common finding across PVOD and PAH, including their experimental models, is a significant decrease in GCN2 expression.
- The study suggests that PVOD and PAH may represent parts of a broader disease spectrum rather than distinct entities, highlighting shared morphologic and biologic similarities.
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