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name: Pulmonary_hypertension
creation_date: '2025-12-04T16:57:31Z'
updated_date: '2026-05-03T00:00:00Z'
category: Cardiovascular Disorder
parents:
- Heart Disease
- Lung Disease
has_subtypes:
- name: Pulmonary Arterial Hypertension (PAH)
subtype_term:
preferred_term: pulmonary arterial hypertension
term:
id: MONDO:0015924
label: pulmonary arterial hypertension
description: A type of pulmonary hypertension characterized by high blood pressure in the arteries that supply the lungs, often idiopathic or associated with other conditions.
- name: Secondary Pulmonary Hypertension
description: Pulmonary hypertension that occurs as a result of other diseases such as left heart disease, chronic lung disease, or thromboembolic disease.
review_notes: >-
MONDO does not have a single term for "secondary pulmonary hypertension" as it
is
a clinical classification. Specific secondary causes have individual terms:
MONDO:0013024 (chronic thromboembolic), MONDO:0017157 (due to lung disease/hypoxia).
prevalence:
- population: Global
percentage: Rare
progression:
- phase: Onset
age_range: Variable, can occur at any age
notes: Presentation depends on underlying cause
genetic:
- name: BMPR2
association: Loss-of-function variants central in heritable and idiopathic PAH
notes: BMPR2 encodes bone morphogenetic protein receptor type 2; impaired BMP/SMAD1/5/9 signaling is a core mechanism in PAH pathogenesis
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene
explanation: Thenappan et al. 2018 establishes that BMPR2 mutations dramatically increase heritable PAH risk.
- reference: PMID:36603064
reference_title: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.
supports: SUPPORT
snippet: loss-of-function mutations in the BMPR2 gene, the most common genetic cause
explanation: Cuthbertson et al. 2023 confirms BMPR2 as the most common genetic cause of PAH with worse prognosis.
- reference: PMID:34023242
reference_title: Significance of BMPR2 mutations in pulmonary arterial hypertension.
supports: SUPPORT
snippet: mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene has been
explanation: Tatius et al. 2021 confirms BMPR2 as the main genetic cause of PAH.
- name: SMAD9
association: TGF-beta/BMP axis component implicated in PAH
notes: Downstream transcription factor in BMP signaling pathway
- name: ACVRL1
association: Implicated in PAH, particularly in hereditary hemorrhagic telangiectasia-associated PAH
notes: Also known as ALK1; encodes activin receptor-like kinase 1, involved in TGF-beta/BMP signaling
- name: ENG
association: Implicated in PAH
notes: Encodes endoglin, a TGF-beta co-receptor involved in vascular development
- name: EIF2AK4
association: Causally linked to pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH)
notes: Also known as GCN2; encodes eukaryotic translation initiation factor 2 alpha kinase 4
- name: KCNK3
association: Ion channel mutations contribute to vasoconstriction and proliferation
notes: Also known as TASK-1; encodes potassium two pore domain channel subfamily K member 3
- name: TBX4
association: Transcriptional regulator contributing to developmental and adult-onset PAH
notes: Encodes T-box transcription factor 4
- name: SOX17
association: Variants associated with severe PAH phenotype
notes: Encodes SRY-box transcription factor 17; regulates vascular development
- name: CAV1
association: Implicated in vascular dysfunction
notes: Encodes caveolin-1, involved in caveolae formation and endothelial signaling
pathophysiology:
- name: Vascular Remodeling
description: Structural changes in the pulmonary vasculature including smooth muscle hypertrophy, intimal proliferation, and fibrosis.
cell_types:
- preferred_term: Smooth Muscle Cell
term:
id: CL:0000192
label: smooth muscle cell
- preferred_term: Endothelial Cell
term:
id: CL:0000115
label: endothelial cell
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
- preferred_term: pericyte
term:
id: CL:0000669
label: pericyte
locations:
- preferred_term: pulmonary artery
term:
id: UBERON:0002012
label: pulmonary artery
biological_processes:
- preferred_term: extracellular matrix organization
term:
id: GO:0030198
label: extracellular matrix organization
- preferred_term: smooth muscle cell proliferation
term:
id: GO:0048661
label: positive regulation of smooth muscle cell proliferation
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: Many cell types are abnormal in PAH, including vascular cells (endothelial
explanation: Thenappan et al. 2018 BMJ review describes the key cell types and structural changes in pulmonary vascular remodeling in PAH.
- reference: PMID:36603064
reference_title: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.
supports: SUPPORT
snippet: progressive remodeling of peripheral pulmonary arteries, caused by the excessive
explanation: Cuthbertson et al. 2023 confirms that excessive proliferation of vascular wall cells drives progressive remodeling in PAH.
- name: Endothelial Dysfunction
description: Endothelial injury and apoptosis with loss of BMPR2/BMP protective signaling; endothelial-to-mesenchymal transition contributing to vascular remodeling.
cell_types:
- preferred_term: Endothelial Cell
term:
id: CL:0000115
label: endothelial cell
locations:
- preferred_term: pulmonary artery
term:
id: UBERON:0002012
label: pulmonary artery
biological_processes:
- preferred_term: endothelial to mesenchymal transition
term:
id: GO:0001837
label: epithelial to mesenchymal transition
- preferred_term: apoptotic process
term:
id: GO:0006915
label: apoptotic process
- preferred_term: BMP signaling pathway
term:
id: GO:0030509
label: BMP signaling pathway
evidence:
- reference: PMID:36603064
reference_title: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: animal models suggests endothelial cell dysfunction is a key initial trigger of
explanation: Cuthbertson et al. 2023 identifies endothelial cell dysfunction as the key initial trigger of pulmonary vascular remodeling with characteristic apoptosis and loss of vasodilatory function.
- reference: PMID:34023242
reference_title: Significance of BMPR2 mutations in pulmonary arterial hypertension.
supports: SUPPORT
snippet: Endothelial dysfunction has been observed in PAH development that results in a
explanation: Tatius et al. 2021 confirms endothelial dysfunction as a key feature of PAH and links it to BMPR2 signaling disruption across multiple vascular cell types.
- name: Inflammation and Immune Activation
description: Perivascular immune cell infiltration and cytokine release fueling proliferative and fibrotic processes.
cell_types:
- preferred_term: macrophage
term:
id: CL:0000235
label: macrophage
locations:
- preferred_term: pulmonary artery
term:
id: UBERON:0002012
label: pulmonary artery
biological_processes:
- preferred_term: inflammatory response
term:
id: GO:0006954
label: inflammatory response
- preferred_term: NF-kappaB signaling
term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence:
- reference: PMID:33105588
reference_title: Perivascular Inflammation in Pulmonary Arterial Hypertension.
supports: SUPPORT
snippet: inflammatory mediators can be detected in PAH patients and correlate with
explanation: Hu et al. 2020 documents the perivascular immune cell infiltrates and elevated cytokines that characterize inflammation in PAH.
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory
explanation: Thenappan et al. 2018 BMJ review describes PAH as partly an autoimmune inflammatory disease with complex cytokine and immune cell changes.
- name: Metabolic Reprogramming
description: Shift from oxidative phosphorylation to glycolysis in vascular cells, supporting proliferation and apoptosis resistance.
cell_types:
- preferred_term: Smooth Muscle Cell
term:
id: CL:0000192
label: smooth muscle cell
- preferred_term: Endothelial Cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: glycolytic process
term:
id: GO:0006096
label: glycolytic process
- preferred_term: oxidative phosphorylation
term:
id: GO:0006119
label: oxidative phosphorylation
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: A cancer-like increase in cell proliferation and resistance to apoptosis
explanation: Thenappan et al. 2018 describes the cancer-like metabolic shift in PAH with mitochondrial abnormalities driving proliferation and apoptosis resistance.
- reference: PMID:36603064
reference_title: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.
supports: SUPPORT
snippet: metabolism, reduced insulin sensitivity, and defective iron handling
explanation: Cuthbertson et al. 2023 details specific metabolic abnormalities in PAH including hyperglycolytic reprogramming and mitochondrial dysfunction.
- name: Hypoxia Signaling
description: Hypoxia-inducible factor (HIF) pathway activation contributing to vasoconstriction and vascular remodeling.
biological_processes:
- preferred_term: response to hypoxia
term:
id: GO:0001666
label: response to hypoxia
- preferred_term: HIF-1-alpha signaling pathway
term:
id: GO:0097411
label: hypoxia-inducible factor-1alpha signaling pathway
- name: Increased Pulmonary Vascular Resistance
description: Result of vascular remodeling and vasoconstriction leading to elevated pressure in the pulmonary artery.
locations:
- preferred_term: pulmonary artery
term:
id: UBERON:0002012
label: pulmonary artery
evidence:
- reference: PMID:30545968
reference_title: Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
supports: SUPPORT
snippet: this 6th WSPH Task Force proposes to include pulmonary
explanation: Simonneau et al. 2019 defines the hemodynamic threshold for pulmonary vascular resistance in the updated PH classification.
- name: Right Ventricular Hypertrophy
description: The right ventricle thickens in response to increased workload from elevated pulmonary arterial pressure.
locations:
- preferred_term: right cardiac ventricle
term:
id: UBERON:0002080
label: heart right ventricle
consequences:
- Right Heart Failure
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: maladaptive changes in the right ventricle, including ischemia and fibrosis
explanation: Thenappan et al. 2018 describes the progression from obstructive remodeling through RV hypertrophy to RV failure in PAH.
downstream:
- target: Right Heart Failure
description: Sustained pulmonary hypertension causes right ventricular remodeling and eventual right heart failure.
evidence:
- reference: PMID:39581144
reference_title: "A new perspective on targeting pulmonary arterial hypertension: Programmed cell death pathways (Autophagy, Pyroptosis, Ferroptosis)."
supports: SUPPORT
snippet: in pulmonary artery pressures, ultimately leading to right-sided heart failure
explanation: This 2024 paper establishes that progressive vascular remodeling in PAH leads to increased resistance and right ventricular failure.
- reference: PMID:36603064
reference_title: BMPR2 Mutation and Metabolic Reprogramming in Pulmonary Arterial Hypertension.
supports: SUPPORT
snippet: ventricular afterload, and progressive right ventricular hypertrophy and heart
explanation: Cuthbertson et al. 2023 confirms the causal chain from increased pulmonary vascular pressures through RV hypertrophy to heart failure.
phenotypes:
- category: Respiratory
name: Dyspnea
frequency: VERY_FREQUENT
diagnostic: true
sequelae:
- target: Reduced Exercise Tolerance
phenotype_term:
preferred_term: Dyspnea
term:
id: HP:0002094
label: Dyspnea
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: with PAH have dyspnea, reduced exercise capacity, exertional syncope, and
explanation: Thenappan et al. 2018 lists dyspnea as a cardinal clinical feature of PAH alongside reduced exercise capacity and exertional syncope.
- category: Cardiovascular
name: Chest Pain
frequency: FREQUENT
phenotype_term:
preferred_term: Chest pain
term:
id: HP:0100749
label: Chest pain
- category: Cardiovascular
name: Syncope
frequency: FREQUENT
notes: Fainting spells associated with exertion.
phenotype_term:
preferred_term: Syncope
term:
id: HP:0001279
label: Syncope
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: with PAH have dyspnea, reduced exercise capacity, exertional syncope, and
explanation: Thenappan et al. 2018 documents exertional syncope as a characteristic presentation of PAH.
- category: Cardiovascular
frequency: FREQUENT
name: Palpitations
phenotype_term:
preferred_term: Palpitations
term:
id: HP:0001962
label: Palpitations
- category: Systemic
frequency: FREQUENT
name: Fatigue
notes: Due to reduced cardiac output
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
- category: Cardiovascular
frequency: OCCASIONAL
name: Edema
notes: Swelling in the legs and ankles
phenotype_term:
preferred_term: Edema
term:
id: HP:0000969
label: Edema
- category: Cardiovascular
name: Reduced Exercise Tolerance
frequency: FREQUENT
phenotype_term:
preferred_term: Reduced Exercise Tolerance
term:
id: HP:0003546
label: Exercise intolerance
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: with PAH have dyspnea, reduced exercise capacity, exertional syncope, and
explanation: Thenappan et al. 2018 lists reduced exercise capacity as a cardinal feature of PAH.
- category: Respiratory
name: Cyanosis
frequency: OCCASIONAL
notes: Bluish discoloration due to inadequate oxygenation
phenotype_term:
preferred_term: Cyanosis
term:
id: HP:0000961
label: Cyanosis
- category: Cardiovascular
name: Right Ventricular Hypertrophy
notes: Develops as a compensatory response to increased pulmonary vascular resistance
phenotype_term:
preferred_term: Right ventricular hypertrophy
term:
id: HP:0001667
label: Right ventricular hypertrophy
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: Obstructive pulmonary vascular remodeling in PAH increases right
explanation: Thenappan et al. 2018 directly links obstructive vascular remodeling to right ventricular hypertrophy as a consequence of increased afterload.
- category: Cardiovascular
name: Tricuspid Regurgitation
notes: Due to right ventricular dilation and annular distortion
phenotype_term:
preferred_term: Tricuspid regurgitation
term:
id: HP:0005180
label: Tricuspid regurgitation
biochemical:
- name: N-terminal pro b-type Natriuretic Peptide (NT-proBNP)
biomarker_term:
preferred_term: NT-proBNP
term:
id: NCIT:C88524
label: N-Terminal Fragment Brain Natriuretic Protein
presence: Elevated
notes: Indicator of right ventricular strain
diagnosis:
- name: Echocardiogram
diagnosis_term:
preferred_term: echocardiography
term:
id: MAXO:0010203
label: echocardiography
notes: Estimates pulmonary artery pressure and evaluates right heart function
- name: Right Heart Catheterization
diagnosis_term:
preferred_term: right heart catheterization
term:
id: MAXO:0035118
label: cardiac catheterization
located_in:
preferred_term: right cardiac chamber
term:
id: UBERON:0035554
label: right cardiac chamber
notes: Definitive test to measure pulmonary artery pressures and confirm diagnosis
evidence:
- reference: PMID:30545968
reference_title: Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
supports: SUPPORT
snippet: catheterisation. Recent data from normal subjects has shown that normal mPAP was
explanation: Simonneau et al. 2019 documents that PH is defined hemodynamically by right heart catheterization measurement of mPAP, with normal mPAP being 14.0 +/- 3.3 mmHg.
environmental:
- name: High-Altitude Exposure
effect: Can exacerbate or trigger symptoms
environment_context:
preferred_term: Mountain environment
term:
id: ENVO:00000081
label: mountain
treatments:
- name: Phosphodiesterase-5 Inhibitors
description: Medications like sildenafil and tadalafil that relax blood vessels in the lungs
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: sildenafil
term:
id: CHEBI:9139
label: sildenafil
- preferred_term: tadalafil
term:
id: CHEBI:71940
label: tadalafil
evidence:
- reference: PMID:29540357
reference_title: "Pulmonary arterial hypertension: pathogenesis and clinical management."
supports: SUPPORT
snippet: antagonists, and soluble guanylate cyclase stimulators), used alone or in
explanation: Thenappan et al. 2018 confirms that PDE5 inhibitors improve functional capacity and hemodynamics in PAH.
- name: Endothelin Receptor Antagonists
description: Medications that block the effects of endothelin and help decrease blood pressure in the lungs
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
- name: Prostacyclin Analogues
description: Medications that mimic the effects of prostacyclin, dilating pulmonary and systemic arterial vascular beds
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Sotatercept
description: >-
Activin-signaling inhibitor added to stable background therapy for pulmonary
arterial hypertension. Phase III STELLAR data showed improved exercise
capacity and multiple secondary endpoints compared with placebo.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: sotatercept
evidence:
- reference: PMID:36877098
reference_title: "Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: sotatercept resulted in a greater improvement in
explanation: >-
STELLAR phase 3 trial supports sotatercept as an effective PAH treatment
when added to stable background therapy.
- name: Oxygen Therapy
description: Used to reduce symptoms in patients with hypoxemia
treatment_term:
preferred_term: artificial respiration
term:
id: MAXO:0000503
label: artificial respiration
- name: Anticoagulation
description: Used particularly in chronic thromboembolic pulmonary hypertension to prevent clotting complications
treatment_term:
preferred_term: cardiovascular agent therapy
term:
id: MAXO:0000181
label: cardiovascular agent therapy
review_notes: Pulmonary hypertension is a complex condition characterized by elevated blood pressure in the pulmonary arteries, leading to right heart strain and failure over time. Symptoms are diverse, with dyspnea, fatigue, and chest pain being common presentations. Diagnosis typically involves imaging and hemodynamic assessments, while treatment focuses on reducing pulmonary pressures and improving symptoms.
disease_term:
preferred_term: pulmonary hypertension
term:
id: MONDO:0005149
label: pulmonary hypertension
references:
- reference: DOI:10.1038/s41392-025-02287-8
title: Signaling pathways and targeted therapy for pulmonary hypertension
findings: []
- reference: DOI:10.1038/s41598-024-64251-w
title: Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats
findings: []
- reference: DOI:10.1164/rccm.202302-0327so
title: 'Pulmonary Hypertension: A Contemporary Review'
findings: []
- reference: DOI:10.31083/j.rcm2506217
title: Roles of LncRNAs in the Pathogenesis of Pulmonary Hypertension
findings: []
Disease Pathophysiology Research Report
Target Disease - Disease Name: Pulmonary hypertension (PH); Pulmonary arterial hypertension (PAH) - MONDO ID: MONDO_0005149 (pulmonary hypertension); PAH (EFO_0001361) - Category: Cardiovascular Disorder
Pathophysiology description (narrative) Pulmonary hypertension is a syndrome defined hemodynamically by mean pulmonary arterial pressure (mPAP) >20 mmHg and increased pulmonary vascular resistance, culminating in right-ventricular (RV) failure. In PAH (Group 1), the small distal pulmonary arteries develop “proliferative, fibrotic, and plexogenic” remodeling on a background of endothelial dysfunction, vasoconstriction, and thrombosis, driven by crosstalk among BMPR2/TGF-β superfamily signaling, inflammation/immune activation, metabolic reprogramming, mitochondrial dysfunction, hypoxia/HIF signaling, ion channel dysregulation, and epigenetic/transcriptional programs. These mechanisms involve pulmonary artery endothelial cells (PAECs), smooth muscle cells (PASMCs), fibroblasts/pericytes, and infiltrating immune cells, and are increasingly considered tractable therapeutic targets, including rebalancing of activin versus BMP signaling (e.g., sotatercept) and inhibition of PDGFRβ signaling (e.g., imatinib/seralutinib) (Sep 2023; American Journal of Respiratory and Critical Care Medicine) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). A 2024 time-course transcriptomic study in rat experimental PH emphasizes the centrality of cell-cycle activation and proliferative programs during progression (Jun 2024; Scientific Reports) (luo2024transcriptomicprofilinghighlights pages 10-11). Recent pathway syntheses also underscore roles for hypoxia/HIF, NF-κB/NLRP3 inflammasome signaling, mitochondrial dysfunction, and endothelial-to-mesenchymal transition as drivers of remodeling and vasculopathy (Signal Transduction and Targeted Therapy, 2025) (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32).
Key concepts and definitions - Hemodynamic definition: PH as mPAP >20 mmHg with elevated PVR; lowered thresholds emphasize early detection (Sep 2023; Am J Respir Crit Care Med) (johnson2023pulmonaryhypertensiona pages 1-2). - Five clinical groups (ESC/ERS 2022): PAH (Group 1), left-heart disease (Group 2), lung disease/hypoxia (Group 3), chronic thromboembolic PH (Group 4), and miscellaneous (Group 5); shared and distinct mechanisms across groups (overview and mechanistic framing) (2025 synthesis citing 2022 guidelines) (aduamankwaah2025signalingpathwaysand pages 1-2).
1) Core Pathophysiology - Primary mechanisms: endothelial dysfunction with apoptosis and clonal expansion; vasoconstriction; proliferative/plexiform arteriopathy; ECM deposition/fibrosis; in situ thrombosis; RV maladaptation (Sep 2023; Am J Respir Crit Care Med) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - Dysregulated molecular pathways: imbalance in TGF-β superfamily tuning of BMP versus activin signaling (BMPR2 axis); growth factor/RTK signaling (e.g., PDGFRβ) driving PASMC/pericyte proliferation; hypoxia/HIF stabilization; inflammatory NF-κB/NLRP3 signaling; metabolic reprogramming (glycolytic shift, mTOR); mitochondrial dysfunction; ion-channel remodeling; epigenetic/transcription factor dysregulation (Sep 2023; Am J Respir Crit Care Med; 2025 pathway synthesis) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4, aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32). - Affected cellular processes: cell-cycle activation and apoptosis resistance in PASMCs and PAECs; EndMT; fibroblast activation; immune cell recruitment and cytokine/growth-factor secretion; ECM remodeling (Sep 2023; Am J Respir Crit Care Med; Jun 2024 Scientific Reports) (johnson2023pulmonaryhypertensiona pages 2-4, luo2024transcriptomicprofilinghighlights pages 10-11).
2) Key Molecular Players - Genes/Proteins (HGNC): - BMPR2 (HGNC:1071) and BMP ligands (BMP9/BMP10) with downstream SMAD1/5/9: loss-of-function variants and signaling impairment are central in heritable and idiopathic PAH; restoration of SMAD1/5 signaling can rescue cellular phenotypes in models (Sep 2023) (johnson2023pulmonaryhypertensiona pages 2-4). - SMAD9 (HGNC:6765), ACVRL1 (ALK1; HGNC:171), ENG (endoglin; HGNC:3349): TGF-β/BMP axis components implicated in PAH (Sep 2023) (johnson2023pulmonaryhypertensiona pages 2-4). - EIF2AK4 (GCN2; HGNC:3255): causally linked to PVOD/PCH (Group 1’); recognized in PH genetics expansions (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2). - KCNK3 (TASK-1; HGNC:11840): ion-channel mutations/aberrant function contribute to vasoconstriction and proliferation (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - TBX4 (HGNC:11574), SOX17 (HGNC:11191): transcriptional regulators contributing to developmental and adult-onset PAH; SOX17 variants associated with severe phenotype (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - CAV1 (HGNC:1527): caveolae/endothelial signaling, implicated in vascular dysfunction (Sep 2023) (johnson2023pulmonaryhypertensiona pages 2-4). - Chemical Entities (CHEBI)/Drugs relevant to mechanisms and trials: - Sotatercept (ligand trap for activins/ActRIIA-Fc): rebalances pro-proliferative activin signaling, advancing outcomes in PAH (2023) (johnson2023pulmonaryhypertensiona pages 1-2). - PDGFR inhibitors: imatinib and inhaled seralutinib are highlighted mechanistically as anti-proliferative approaches targeting PASMC/pericyte expansion (2023) (johnson2023pulmonaryhypertensiona pages 1-2). - Cell Types (CL): PAECs (CL:0000115); PASMCs (CL:0000746); adventitial fibroblasts (CL:0002553); pericytes (CL:0000669); macrophages and other immune cells (multiple CL terms) (mechanistic framing) (johnson2023pulmonaryhypertensiona pages 1-2, aduamankwaah2025signalingpathwaysand pages 1-2). - Anatomical Locations (UBERON): small pulmonary arterioles (UBERON:0001981), pulmonary artery (UBERON:0002114), right ventricle (UBERON:0002080) (johnson2023pulmonaryhypertensiona pages 2-4).
3) Biological Processes (GO) disrupted - TGF-β receptor signaling pathway; BMP signaling (GO:0007179, GO:0030509) - Positive regulation of cell proliferation; cell cycle process (GO:0042127, GO:0022402) supported by in vivo transcriptomics in progressive PH (Jun 2024) (luo2024transcriptomicprofilinghighlights pages 10-11) - Endothelial to mesenchymal transition (GO:0001837); regulation of apoptosis (GO:0042981) (aduamankwaah2025signalingpathwaysand pages 1-2, johnson2023pulmonaryhypertensiona pages 1-2) - Response to hypoxia; HIF signaling (GO:0001666) (aduamankwaah2025signalingpathwaysand pages 1-2) - Inflammatory response; NF-κB signaling; NLRP3 inflammasome activation (GO:0006954; pathway-level evidence) (aduamankwaah2025signalingpathwaysand pages 31-32) - Mitochondrial organization; oxidative phosphorylation vs glycolysis switch (GO:0007005; GO:0006119/GO:0006096) (aduamankwaah2025signalingpathwaysand pages 1-2) - Ion transmembrane transport (K+ channel activity; GO:0005267) (johnson2023pulmonaryhypertensiona pages 2-4) - Epigenetic regulation of gene expression (GO:0040029) and lncRNA-mediated regulation (mechanistic overview, 2024) (liu2024rolesoflncrnas pages 1-2)
4) Cellular Components (GOCC) - Plasma membrane/caveolae (CAV1) (GO:0005886; GO:0005901) (johnson2023pulmonaryhypertensiona pages 2-4) - Cytosol and nucleus (SMAD translocation; transcription factor activity) (johnson2023pulmonaryhypertensiona pages 2-4) - Mitochondrion (metabolic/ROS signaling) (aduamankwaah2025signalingpathwaysand pages 1-2) - Extracellular space/ECM (fibrosis/remodeling) (johnson2023pulmonaryhypertensiona pages 2-4)
5) Disease Progression (sequence of events) - Initiation: endothelial injury and apoptosis with loss of BMPR2/BMP protective signaling; early vasoconstriction from ion-channel changes and NO/prostacyclin–endothelin imbalance (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - Propagation: EndMT; PASMC and fibroblast proliferation and survival (cell-cycle activation); ECM deposition and occlusive (“plexiform”) lesions; perivascular immune infiltration fueling cytokine/growth-factor loops; metabolic reprogramming and mitochondrial dysfunction reinforce proliferation and apoptosis resistance (Sep 2023; Jun 2024) (johnson2023pulmonaryhypertensiona pages 2-4, luo2024transcriptomicprofilinghighlights pages 10-11). - Clinical manifestation: progressive elevation of PVR and mPAP, RV hypertrophy/dysfunction and failure (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4).
6) Phenotypic Manifestations (HP terms) - Dyspnea on exertion (HP:0002875), fatigue (HP:0012378), syncope (HP:0001279), chest pain (HP:0100749), peripheral edema (HP:0002615), cyanosis (HP:0000979), right heart failure (HP:0001631). These phenotypes mechanistically reflect increased RV afterload from pulmonary vasculopathy and vasoconstriction (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4).
Recent developments and latest research (2023–2024 priority) with therapeutic implications - Activin-BMP axis and disease modification: “sotatercept is presented as a first-in-class activin signaling inhibitor that rebalances TGF-β signaling by inhibiting proproliferative activins,” and has demonstrated clinical benefit in PAH on background therapy (Sep 2023, Am J Respir Crit Care Med; DOI: https://doi.org/10.1164/rccm.202302-0327so) (johnson2023pulmonaryhypertensiona pages 1-2). - PDGFRβ signaling and anti-proliferative strategies: PDGFRβ signaling is implicated in PASMC/pericyte proliferation and apoptosis resistance; “PDGFRβ inhibitors such as imatinib and seralutinib are noted as promising therapeutic approaches” (Sep 2023; DOI above) (johnson2023pulmonaryhypertensiona pages 1-2). - Cell-cycle and proliferative programs in progression: longitudinal lung RNA-seq in monocrotaline rat PH shows progressive upregulation of proliferation markers (e.g., PCNA, Ccna2, Top2a) and enrichment of cell-cycle/innate immune pathways (Jun 2024; DOI: https://doi.org/10.1038/s41598-024-64251-w) (luo2024transcriptomicprofilinghighlights pages 10-11). - Epigenetics/lncRNAs: lncRNAs are differentially expressed in PH and influence PAEC/PASMC proliferation, apoptosis, EndMT, mitochondrial function, and inflammation, supporting their roles as biomarkers and mechanistic targets (Jun 2024; Reviews in Cardiovasc Med; DOI: https://doi.org/10.31083/j.rcm2506217) (liu2024rolesoflncrnas pages 1-2).
Current applications and real-world implementations (selected examples with pathophysiology links) - Pathway-directed therapy beyond vasodilators: clinical advances with sotatercept (activin signaling trap) reflect targeting of a core disease pathway (TGF-β superfamily imbalance) (Sep 2023) (johnson2023pulmonaryhypertensiona pages 1-2). Anti-proliferative RTK inhibition (PDGFRβ) is an active area (imatinib/seralutinib) (johnson2023pulmonaryhypertensiona pages 1-2). - Mechanistic targets under study/preclinical support: NF-κB/NLRP3 inflammasome inhibition, PI3K/Akt/mTOR modulation, and HIF pathway interventions are recurrent strategies in preclinical/early translational literature (2025 synthesis of 20+ pathways) (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32).
Expert opinions and analysis from authoritative sources - A 2023 state-of-the-art review (Am J Respir Crit Care Med) synthesizes PH pathogenesis across endothelial dysfunction, inflammation/immunity, metabolism/oxidant stress, hypoxia signaling, mitochondrial dysfunction, ion channels, and epigenetics/transcription, and highlights disease-modifying therapeutic concepts (e.g., sotatercept) (Sep 2023; DOI: https://doi.org/10.1164/rccm.202302-0327so) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - A comprehensive translational pathway review (Signal Transduction and Targeted Therapy, 2025) catalogs approximately twenty signaling axes implicated in PH and aligns multiple therapeutic modalities (gene, cell, pharmacological) to these pathways (Jul 2025; DOI: https://doi.org/10.1038/s41392-025-02287-8) (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32).
Relevant statistics and data from recent studies - Transcriptomics in experimental PH: progressive DEGs rising from 1,038 at week 1 to 3,125 at week 3 (P<0.05; |log2FC|>log2 1.5), with validation of proliferation markers (PCNA, Ccna2, Top2a) by Western blot and immunofluorescence, supporting a central role for cell proliferation in PH progression (Jun 2024; GEO GSE229361; DOI: https://doi.org/10.1038/s41598-024-64251-w) (luo2024transcriptomicprofilinghighlights pages 10-11).
Evidence items (selected with PMIDs/URLs/dates) - Johnson et al., 2023. Pulmonary Hypertension: A Contemporary Review. Am J Respir Crit Care Med. Sep 1, 2023. DOI: https://doi.org/10.1164/rccm.202302-0327so (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4) • Quote (framing): PAH involves “proliferative, fibrotic, and plexogenic remodeling of distal pulmonary arterioles,” with genetic/epigenetic drivers and dysregulated TGF-β/BMP signaling; activin inhibition (sotatercept) rebalances TGF-β signaling; PDGFRβ signaling in PASMC/pericytes is a therapeutic target (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4). - Luo et al., 2024. Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats. Scientific Reports. Jun 2024. DOI: https://doi.org/10.1038/s41598-024-64251-w (luo2024transcriptomicprofilinghighlights pages 10-11) • Data: stepwise increase in significant DEGs (1,038 → 1,244 → 3,125 over weeks 1–3), enrichment for cell-cycle/innate immune pathways; validation of PCNA, Ccna2, Top2a upregulation (luo2024transcriptomicprofilinghighlights pages 10-11). - Liu et al., 2024. Roles of LncRNAs in the Pathogenesis of Pulmonary Hypertension. Reviews in Cardiovascular Medicine. Jun 17, 2024. DOI: https://doi.org/10.31083/j.rcm2506217 (liu2024rolesoflncrnas pages 1-2) • Quote (summary): lncRNAs “are differentially expressed in PH” and regulate PAEC/PASMC proliferation, apoptosis resistance, EndMT, mitochondrial function and inflammation, suggesting biomarker and therapeutic potential (liu2024rolesoflncrnas pages 1-2). - Adu‑Amankwaah et al., 2025. Signaling pathways and targeted therapy for pulmonary hypertension. Signal Transduction and Targeted Therapy. Jul 2025. DOI: https://doi.org/10.1038/s41392-025-02287-8 (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32) • Quote (overview): targeting aberrant signaling hubs across HIF, NF‑κB/NLRP3, BMPR2/SMAD and others offers “great potential for mitigating PH pathology,” with qualitative reductions in mPAP/RVSP across preclinical interventions (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 31-32).
Ontology-structured annotations - Gene/protein annotations (HGNC → process/location): • BMPR2 (HGNC:1071): BMP signaling; SMAD1/5/9 activation; plasma membrane→nucleus; negative regulation of PASMC proliferation (johnson2023pulmonaryhypertensiona pages 2-4) • SMAD9 (HGNC:6765): BMP pathway transcription factor; nucleus; regulation of transcription (johnson2023pulmonaryhypertensiona pages 2-4) • ACVRL1/ENG (HGNC:171/3349): endothelial TGF-β/BMP signaling; plasma membrane/caveolae; vascular development (johnson2023pulmonaryhypertensiona pages 2-4) • EIF2AK4 (HGNC:3255): integrated stress response kinase; PVOD/PCH genetics; cytosol (johnson2023pulmonaryhypertensiona pages 1-2) • KCNK3 (HGNC:11840): K+ leak channel; ion transport; membrane potential; PASMC contraction/proliferation (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4) • TBX4 (HGNC:11574), SOX17 (HGNC:11191): transcriptional control of vascular development; nucleus (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4) • CAV1 (HGNC:1527): caveolae scaffolding protein; endothelial signaling; caveolae (johnson2023pulmonaryhypertensiona pages 2-4) - Cell type involvement (CL): PAECs (CL:0000115), PASMCs (CL:0000746), adventitial fibroblasts (CL:0002553), pericytes (CL:0000669), macrophages (CL:0000235) (johnson2023pulmonaryhypertensiona pages 1-2, aduamankwaah2025signalingpathwaysand pages 1-2) - Anatomical locations (UBERON): small pulmonary artery/arteriole (UBERON:0001981), pulmonary artery (UBERON:0002114), right ventricle (UBERON:0002080) (johnson2023pulmonaryhypertensiona pages 2-4) - Chemical entities (CHEBI) relevant to mechanisms: prostacyclin analogs, endothelin receptor antagonists, PDE5 inhibitors (standard of care; class framing) and disease-modifying examples (sotatercept; PDGFR inhibitors) (johnson2023pulmonaryhypertensiona pages 1-2)
Notes and limitations - Where possible, we prioritized 2023–2024 primary and review sources. For pathway breadth and preclinical intervention mapping, we cited a 2025 comprehensive synthesis when 2023–2024 sources did not explicitly enumerate comparable cross-pathway tables (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 31-32). Additional quantitative clinical-trial effect sizes (e.g., for TORREY seralutinib, Phase 3 sotatercept) were not detailed here because those specific datasets were not among the retrieved texts; however, mechanistic and trial‑framing statements are supported (johnson2023pulmonaryhypertensiona pages 1-2).
References (with persistent links) - Johnson et al., 2023. Am J Respir Crit Care Med. DOI: https://doi.org/10.1164/rccm.202302-0327so (Sep 1, 2023) (johnson2023pulmonaryhypertensiona pages 1-2, johnson2023pulmonaryhypertensiona pages 2-4) - Luo et al., 2024. Scientific Reports. DOI: https://doi.org/10.1038/s41598-024-64251-w (Jun 2024) (luo2024transcriptomicprofilinghighlights pages 10-11) - Liu et al., 2024. Reviews in Cardiovascular Medicine. DOI: https://doi.org/10.31083/j.rcm2506217 (Jun 17, 2024) (liu2024rolesoflncrnas pages 1-2) - Adu‑Amankwaah et al., 2025. Signal Transduction and Targeted Therapy. DOI: https://doi.org/10.1038/s41392-025-02287-8 (Jul 2025) (aduamankwaah2025signalingpathwaysand pages 1-2, aduamankwaah2025signalingpathwaysand pages 29-30, aduamankwaah2025signalingpathwaysand pages 31-32)
References
(johnson2023pulmonaryhypertensiona pages 1-2): Shelsey Johnson, Natascha Sommer, Katherine Cox-Flaherty, Norbert Weissmann, Corey E. Ventetuolo, and Bradley A. Maron. Pulmonary hypertension: a contemporary review. American Journal of Respiratory and Critical Care Medicine, 208:528-548, Sep 2023. URL: https://doi.org/10.1164/rccm.202302-0327so, doi:10.1164/rccm.202302-0327so. This article has 130 citations and is from a highest quality peer-reviewed journal.
(johnson2023pulmonaryhypertensiona pages 2-4): Shelsey Johnson, Natascha Sommer, Katherine Cox-Flaherty, Norbert Weissmann, Corey E. Ventetuolo, and Bradley A. Maron. Pulmonary hypertension: a contemporary review. American Journal of Respiratory and Critical Care Medicine, 208:528-548, Sep 2023. URL: https://doi.org/10.1164/rccm.202302-0327so, doi:10.1164/rccm.202302-0327so. This article has 130 citations and is from a highest quality peer-reviewed journal.
(luo2024transcriptomicprofilinghighlights pages 10-11): Ang Luo, Rongrong Hao, Xia Zhou, Yangfan Jia, Changlei Bao, Lei Yang, Lirong Zhou, Chenxin Gu, Ankit A. Desai, Haiyang Tang, and Ai-ai Chu. Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats. Scientific Reports, Jun 2024. URL: https://doi.org/10.1038/s41598-024-64251-w, doi:10.1038/s41598-024-64251-w. This article has 5 citations and is from a peer-reviewed journal.
(aduamankwaah2025signalingpathwaysand pages 1-2): J. Adu-Amankwaah, Yue Shi, Hequn Song, Yixuan Ma, Jia Liu, Hao Wang, Jinxiang Yuan, Kun Sun, Qinghua Hu, and Rubin Tan. Signaling pathways and targeted therapy for pulmonary hypertension. Signal Transduction and Targeted Therapy, Jul 2025. URL: https://doi.org/10.1038/s41392-025-02287-8, doi:10.1038/s41392-025-02287-8. This article has 10 citations and is from a peer-reviewed journal.
(aduamankwaah2025signalingpathwaysand pages 29-30): J. Adu-Amankwaah, Yue Shi, Hequn Song, Yixuan Ma, Jia Liu, Hao Wang, Jinxiang Yuan, Kun Sun, Qinghua Hu, and Rubin Tan. Signaling pathways and targeted therapy for pulmonary hypertension. Signal Transduction and Targeted Therapy, Jul 2025. URL: https://doi.org/10.1038/s41392-025-02287-8, doi:10.1038/s41392-025-02287-8. This article has 10 citations and is from a peer-reviewed journal.
(aduamankwaah2025signalingpathwaysand pages 31-32): J. Adu-Amankwaah, Yue Shi, Hequn Song, Yixuan Ma, Jia Liu, Hao Wang, Jinxiang Yuan, Kun Sun, Qinghua Hu, and Rubin Tan. Signaling pathways and targeted therapy for pulmonary hypertension. Signal Transduction and Targeted Therapy, Jul 2025. URL: https://doi.org/10.1038/s41392-025-02287-8, doi:10.1038/s41392-025-02287-8. This article has 10 citations and is from a peer-reviewed journal.
(liu2024rolesoflncrnas pages 1-2): Ting Liu, Shuang-Lan Xu, Jiao Yang, and Xiqian Xing. Roles of lncrnas in the pathogenesis of pulmonary hypertension. Reviews in Cardiovascular Medicine, Jun 2024. URL: https://doi.org/10.31083/j.rcm2506217, doi:10.31083/j.rcm2506217. This article has 1 citations and is from a peer-reviewed journal.