Pulmonary_hypertension

◆

Subtypes

2

Pulmonary Arterial Hypertension (PAH) MONDO:0015924

A type of pulmonary hypertension characterized by high blood pressure in the arteries that supply the lungs, often idiopathic or associated with other conditions.

Secondary Pulmonary Hypertension

Pulmonary hypertension that occurs as a result of other diseases such as left heart disease, chronic lung disease, or thromboembolic disease.

⚙

Pathophysiology

7

Vascular Remodeling

Structural changes in the pulmonary vasculature including smooth muscle hypertrophy, intimal proliferation, and fibrosis.

Smooth Muscle Cell CL:0000192 Endothelial Cell CL:0000115 fibroblast CL:0000057 pericyte CL:0000669

extracellular matrix organization GO:0030198 smooth muscle cell proliferation GO:0048661

pulmonary artery UBERON:0002012

Downstream

Increased Pulmonary Vascular Resistance Medial hypertrophy, intimal proliferation, and fibrosis narrow and obliterate the small pulmonary arteries, which is the structural basis of the rise in pulmonary vascular resistance.

Show evidence (2 references)

PMID:29540357 SUPPORT

"Many cell types are abnormal in PAH, including vascular cells (endothelial"

Thenappan et al. 2018 BMJ review describes the key cell types and structural changes in pulmonary vascular remodeling in PAH.

PMID:36603064 SUPPORT

"progressive remodeling of peripheral pulmonary arteries, caused by the excessive"

Cuthbertson et al. 2023 confirms that excessive proliferation of vascular wall cells drives progressive remodeling in PAH.

Endothelial Dysfunction

Endothelial injury and apoptosis with loss of BMPR2/BMP protective signaling; endothelial-to-mesenchymal transition contributing to vascular remodeling.

Endothelial Cell CL:0000115

endothelial to mesenchymal transition GO:0001837 apoptotic process GO:0006915 BMP signaling pathway GO:0030509

pulmonary artery UBERON:0002012

Downstream

Vascular Remodeling Endothelial injury, apoptosis, and endothelial-to-mesenchymal transition with loss of protective BMPR2 signaling initiate the proliferative remodeling of the small pulmonary arteries.

Increased Pulmonary Vascular Resistance Loss of endothelial vasodilator output and excess vasoconstrictor mediators raise pulmonary arterial tone directly, before and alongside the structural remodeling.

Show evidence (2 references)

PMID:36603064 SUPPORT Model Organism

"animal models suggests endothelial cell dysfunction is a key initial trigger of"

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.

PMID:34023242 SUPPORT

"Endothelial dysfunction has been observed in PAH development that results in a"

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.

Inflammation and Immune Activation

Perivascular immune cell infiltration and cytokine release fueling proliferative and fibrotic processes.

macrophage CL:0000235

inflammatory response GO:0006954 NF-kappaB signaling GO:0007249

pulmonary artery UBERON:0002012

Downstream

Vascular Remodeling Perivascular macrophage and lymphocyte infiltration with sustained cytokine release is what fuels the proliferative and fibrotic changes in the vessel wall.

Show evidence (2 references)

PMID:33105588 SUPPORT

"inflammatory mediators can be detected in PAH patients and correlate with"

Hu et al. 2020 documents the perivascular immune cell infiltrates and elevated cytokines that characterize inflammation in PAH.

PMID:29540357 SUPPORT

"and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory"

Thenappan et al. 2018 BMJ review describes PAH as partly an autoimmune inflammatory disease with complex cytokine and immune cell changes.

Metabolic Reprogramming

Shift from oxidative phosphorylation to glycolysis in vascular cells, supporting proliferation and apoptosis resistance.

Smooth Muscle Cell CL:0000192 Endothelial Cell CL:0000115

glycolytic process GO:0006096 oxidative phosphorylation GO:0006119

Downstream

Vascular Remodeling The glycolytic shift sustains the proliferation and apoptosis resistance of pulmonary vascular smooth muscle and endothelial cells that build the remodeled vessel wall.

Show evidence (2 references)

PMID:29540357 SUPPORT

"A cancer-like increase in cell proliferation and resistance to apoptosis"

Thenappan et al. 2018 describes the cancer-like metabolic shift in PAH with mitochondrial abnormalities driving proliferation and apoptosis resistance.

PMID:36603064 SUPPORT

"metabolism, reduced insulin sensitivity, and defective iron handling"

Cuthbertson et al. 2023 details specific metabolic abnormalities in PAH including hyperglycolytic reprogramming and mitochondrial dysfunction.

Hypoxia Signaling

Hypoxia-inducible factor (HIF) pathway activation contributing to vasoconstriction and vascular remodeling.

response to hypoxia GO:0001666 HIF-1-alpha signaling pathway GO:0097411

Downstream

Increased Pulmonary Vascular Resistance Hypoxia constricts the pulmonary arterioles acutely, raising resistance before any structural change has occurred.

Vascular Remodeling Sustained HIF pathway activation drives the proliferative smooth-muscle and matrix changes that convert reversible hypoxic vasoconstriction into fixed remodeling.

Increased Pulmonary Vascular Resistance

Result of vascular remodeling and vasoconstriction leading to elevated pressure in the pulmonary artery.

pulmonary artery UBERON:0002012

Downstream

Right Ventricular Hypertrophy Elevated resistance raises the pressure the right ventricle must generate at every beat, and the ventricle hypertrophies in response to that afterload.

Dyspnea A pulmonary circulation that cannot accommodate an increase in flow caps the cardiac output achievable on exertion, which is experienced as breathlessness.

Show evidence (1 reference)

PMID:30545968 SUPPORT

"this 6th WSPH Task Force proposes to include pulmonary"

Simonneau et al. 2019 defines the hemodynamic threshold for pulmonary vascular resistance in the updated PH classification.

Right Ventricular Hypertrophy

The right ventricle thickens in response to increased workload from elevated pulmonary arterial pressure.

right cardiac ventricle UBERON:0002080

Downstream

Right Heart Failure Sustained pulmonary hypertension causes right ventricular remodeling and eventual right heart failure.

Tricuspid Regurgitation As the pressure-loaded right ventricle dilates, the tricuspid annulus is distorted and the leaflets no longer coapt.

Edema Once the right ventricle decompensates, raised right-sided filling pressures are transmitted into the systemic venous bed and produce dependent oedema.

Fatigue A right ventricle that cannot deliver an adequate cardiac output limits systemic oxygen delivery, which patients report as persistent tiredness.

Syncope When the fixed pulmonary vascular resistance prevents any rise in cardiac output on exertion, cerebral perfusion falls and exertional syncope results.

Chest Pain The hypertrophied, high-pressure right ventricle outgrows its coronary supply, and the resulting subendocardial ischaemia presents as chest pain.

Palpitations Right atrial and ventricular dilatation provides the substrate for the supraventricular arrhythmias that patients perceive as palpitations.

Cyanosis Low cardiac output with a widened arteriovenous oxygen difference, and in some patients right-to-left shunting through a patent foramen ovale, produce visible cyanosis.

Show evidence (1 reference)

PMID:29540357 SUPPORT

"maladaptive changes in the right ventricle, including ischemia and fibrosis"

Thenappan et al. 2018 describes the progression from obstructive remodeling through RV hypertrophy to RV failure in PAH.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Target 'Right Heart Failure' (from 'Right Ventricular Hypertrophy') not found in named elements

●

Phenotypes

10

Cardiovascular 2

Syncope FREQUENT HP:0001279

Fainting spells associated with exertion.

Show evidence (1 reference)

PMID:29540357 SUPPORT

"with PAH have dyspnea, reduced exercise capacity, exertional syncope, and"

Thenappan et al. 2018 documents exertional syncope as a characteristic presentation of PAH.

Palpitations FREQUENT HP:0001962

Integument 1

Cyanosis OCCASIONAL HP:0000961

Bluish discoloration due to inadequate oxygenation

Metabolism 1

Edema OCCASIONAL HP:0000969

Swelling in the legs and ankles

Respiratory 1

Dyspnea VERY_FREQUENT HP:0002094

Sequelae: Reduced Exercise Tolerance

Show evidence (1 reference)

PMID:29540357 SUPPORT

"with PAH have dyspnea, reduced exercise capacity, exertional syncope, and"

Thenappan et al. 2018 lists dyspnea as a cardinal clinical feature of PAH alongside reduced exercise capacity and exertional syncope.

Constitutional 3

Chest Pain FREQUENT HP:0100749

Fatigue FREQUENT HP:0012378

Due to reduced cardiac output

Reduced Exercise Tolerance FREQUENT Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:29540357 SUPPORT

"with PAH have dyspnea, reduced exercise capacity, exertional syncope, and"

Thenappan et al. 2018 lists reduced exercise capacity as a cardinal feature of PAH.

Other 2

Right Ventricular Hypertrophy HP:0001667

Develops as a compensatory response to increased pulmonary vascular resistance

Show evidence (1 reference)

PMID:29540357 SUPPORT

"Obstructive pulmonary vascular remodeling in PAH increases right"

Thenappan et al. 2018 directly links obstructive vascular remodeling to right ventricular hypertrophy as a consequence of increased afterload.

Tricuspid Regurgitation HP:0005180

Due to right ventricular dilation and annular distortion

🧬

Genetic Associations

9

BMPR2 (Loss-of-function variants central in heritable and idiopathic PAH)

Gene: BMPR2 hgnc:1078

Show evidence (3 references)

PMID:29540357 SUPPORT

"Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene"

Thenappan et al. 2018 establishes that BMPR2 mutations dramatically increase heritable PAH risk.

PMID:36603064 SUPPORT

"loss-of-function mutations in the BMPR2 gene, the most common genetic cause"

Cuthbertson et al. 2023 confirms BMPR2 as the most common genetic cause of PAH with worse prognosis.

PMID:34023242 SUPPORT

"mutation in the bone morphogenetic protein receptor 2 (BMPR2) gene has been"

Tatius et al. 2021 confirms BMPR2 as the main genetic cause of PAH.

SMAD9 (TGF-beta/BMP axis component implicated in PAH)

Gene: SMAD9 hgnc:6774

ACVRL1 (Implicated in PAH, particularly in hereditary hemorrhagic telangiectasia-associated PAH)

Gene: ACVRL1 hgnc:175

ENG (Implicated in PAH)

Gene: ENG hgnc:3349

EIF2AK4 (Causally linked to pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH))

Gene: EIF2AK4 hgnc:19687

KCNK3 (Ion channel mutations contribute to vasoconstriction and proliferation)

Gene: KCNK3 hgnc:6278

TBX4 (Transcriptional regulator contributing to developmental and adult-onset PAH)

Gene: TBX4 hgnc:11603

SOX17 (Variants associated with severe PAH phenotype)

Gene: SOX17 hgnc:18122

CAV1 (Implicated in vascular dysfunction)

Gene: CAV1 hgnc:1527

💊

Medical Actions

7

Phosphodiesterase-5 Inhibitors

Action: Pharmacotherapy NCIT:C15986

Agent: sildenafil CHEBI:9139 tadalafil CHEBI:71940

Medications like sildenafil and tadalafil that relax blood vessels in the lungs

Mechanism Target:

INHIBITS Increased Pulmonary Vascular Resistance — Blocking cGMP breakdown in pulmonary vascular smooth muscle sustains nitric-oxide-mediated vasodilation and lowers pulmonary vascular resistance.

Show evidence (1 reference)

PMID:29540357 SUPPORT

"antagonists, and soluble guanylate cyclase stimulators), used alone or in"

Thenappan et al. 2018 confirms that PDE5 inhibitors improve functional capacity and hemodynamics in PAH.

Endothelin Receptor Antagonists

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Medications that block the effects of endothelin and help decrease blood pressure in the lungs

Mechanism Target:

INHIBITS Increased Pulmonary Vascular Resistance — Endothelin receptor blockade removes one arm of the vasoactive mediator imbalance produced by the dysfunctional endothelium, lowering pulmonary arterial tone.

MODULATES Endothelial Dysfunction — The drug acts on the consequences of endothelial mediator imbalance rather than repairing the endothelium, so it modulates this node rather than restoring it.

Prostacyclin Analogues

Action: Pharmacotherapy NCIT:C15986

Medications that mimic the effects of prostacyclin, dilating pulmonary and systemic arterial vascular beds

Mechanism Target:

INHIBITS Increased Pulmonary Vascular Resistance — Replacing the prostacyclin the dysfunctional endothelium no longer makes dilates the pulmonary arterial bed and lowers resistance.

Sotatercept

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: sotatercept NCIT:C80038

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.

Mechanism Target:

INHIBITS Vascular Remodeling — Sotatercept is an activin-signaling ligand trap; rebalancing pro-growth activin against protective BMP signaling targets the proliferative remodeling itself rather than pulmonary arterial tone.

Show evidence (1 reference)

PMID:36877098 SUPPORT Human Clinical

"sotatercept resulted in a greater improvement in"

STELLAR phase 3 trial supports sotatercept as an effective PAH treatment when added to stable background therapy.

Oxygen Therapy

Action: Oxygen Therapy NCIT:C94624

Used to reduce symptoms in patients with hypoxemia

Mechanism Target:

INHIBITS Hypoxia Signaling — Raising alveolar oxygen tension removes the hypoxic stimulus for HIF pathway activation and hypoxic pulmonary vasoconstriction.

INHIBITS Cyanosis — Supplemental oxygen raises arterial saturation, which is the symptomatic benefit in hypoxaemic patients.

Anticoagulation

Action: cardiovascular agent therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Used particularly in chronic thromboembolic pulmonary hypertension to prevent clotting complications

Mechanism Target:

INHIBITS Increased Pulmonary Vascular Resistance — In chronic thromboembolic pulmonary hypertension anticoagulation prevents further thromboembolic obstruction from adding to the fixed resistance; it does not act on the vasoconstrictive or remodeling mechanisms this entry otherwise models, and this entry carries no thromboembolic obstruction node for it to target directly.

Balloon Pulmonary Angioplasty

Action: balloon pulmonary angioplasty Ontology label: Percutaneous Transluminal Angioplasty NCIT:C217465

Catheter-based interventional treatment for chronic thromboembolic pulmonary hypertension (CTEPH), particularly in patients with inoperable or distal-vessel disease or persistent pulmonary hypertension after pulmonary endarterectomy. Serial balloon dilation of stenotic/occluded pulmonary arteries reduces pulmonary vascular resistance and improves functional capacity.

Mechanism Target:

INHIBITS Increased Pulmonary Vascular Resistance — Serial balloon dilation reopens stenotic and occluded pulmonary arteries in chronic thromboembolic disease, mechanically lowering the fixed component of pulmonary vascular resistance.

Show evidence (1 reference)

PMID:42055655 SUPPORT Human Clinical

"Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life."

Reports improvement in pulmonary vascular resistance itself, which is the node this treatment link targets.

Show evidence (2 references)

PMID:42055655 SUPPORT Human Clinical

"Balloon pulmonary angioplasty (BPA) has emerged as a very effective therapeutic option in these patients."

The BPA-CTEPH Alliance statement establishes balloon pulmonary angioplasty as an effective therapeutic option for chronic thromboembolic pulmonary hypertension.

PMID:42055655 SUPPORT Human Clinical

"Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life."

Quantifies the hemodynamic and functional benefit of BPA in CTEPH.

🌍

Environmental Factors

1

High-Altitude Exposure

Show evidence (2 references)

PMID:33578749 SUPPORT Human Clinical

"Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension."

Names pulmonary hypertension as a cardio-pulmonary consequence of the alveolar hypoxia that defines the high-altitude environment, which is the association this exposure entry asserts.

PMID:33578749 SUPPORT Human Clinical

"Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure."

Gives the route from the exposure to the disease and on to right heart failure, distinguishing sustained exposure, which remodels the pulmonary vasculature, from the acute vasoconstrictive response.

Mechanism Target:

TRIGGERS Hypoxia Signaling — The alveolar hypoxia that defines the high-altitude environment is the stimulus that activates the HIF pathway and hypoxic pulmonary vasoconstriction.

Show evidence (1 reference)

PMID:33578749 SUPPORT Human Clinical

"Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension."

Names alveolar hypoxia as the operative feature of the high-altitude environment and pulmonary hypertension as its cardio-pulmonary consequence, which is the exposure-to-mechanism step asserted here.

TRIGGERS Vascular Remodeling — Sustained rather than acute high-altitude exposure converts reversible hypoxic vasoconstriction into fixed remodeling of the pulmonary vasculature.

Show evidence (1 reference)

PMID:33578749 SUPPORT Human Clinical

"Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure."

States that chronic hypoxic exposure induces pulmonary vascular remodeling, which is exactly the exposure-to-mechanism link on this edge.

🔬

Biochemical Markers

1

N-terminal pro b-type Natriuretic Peptide (NT-proBNP) (Elevated)

Pathograph Readouts

Readout Of Right Ventricular Hypertrophy Positive Monitoring

Natriuretic peptide release tracks right ventricular wall stress, so the circulating level reports the load on the pressure-overloaded right ventricle rather than the pulmonary vascular lesion itself.

🔬

Diagnosis

2

Echocardiogram

echocardiography NCIT:C16525

Estimates pulmonary artery pressure and evaluates right heart function

Right Heart Catheterization

right heart catheterization NCIT:C38044

Definitive test to measure pulmonary artery pressures and confirm diagnosis

Show evidence (1 reference)

PMID:30545968 SUPPORT

"catheterisation. Recent data from normal subjects has shown that normal mPAP was"

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.

📈

Progression

1

Onset

Age: Variable, can occur at any age

Presentation depends on underlying cause

📊

Prevalence

1

Global

Rare Rare

📊

Related Datasets

8

Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIP-seq] geo:GSE126322

Pulmonary Arterial Hypertension (PAH) is a cardiovascular disease characterized by progressively increasing blood pressure as a result of obliteration and loss of pulmonary arteries. We have extracted pulmonary arterial endothelial cells from lungs of a cohort of PAH patients (n=10) and controls (n=9), cultured the cells for 3-5 passages, and performed chromatin (H3K27ac, H3K4me1, and H3K4me3 ChIP-Seq), expression (RNA-Seq) and chromatin interaction profiling (ChIA-PET). We observed a large-scale remodelling of the active chromatin landscape at enhancers while promoters and gene expression remained unchanged.

human CHIP SEQ n=55

PMID:32245974

Identified by GEO DataSets index search for Pulmonary hypertension (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Global knockout of melanoma differentiation-associated protein 5 protects mice from chronic hypoxia/SU5416-induced pulmonary hypertension geo:GSE314466

Pulmonary arterial hypertension (PAH) is a severe disease affecting the pulmonary arteries, causing increased blood pressure due to narrowing of the pulmonary artery lumen. Aberrant proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs), along with a dysregulation of the immune response, contributes to arterial remodeling. We hypothesized that the cytosolic RNA receptor melanoma differentiation-associated protein 5 (MDA5) contributes to PAH by dysregulating pulmonary vascular cell function and immune cell response. In lung tissue from control patients and PAH patients, MDA5 immunoreactivity was widely distributed throughout the pulmonary artery wall.

human BULK RNA SEQ n=6

PMID:42030239

Identified by GEO DataSets index search for Pulmonary hypertension (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

High Altitude Pulmonary Hypertension ega:EGAS00001003155

The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.

human WGS

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

High Altitude Pulmonary Hypertension ega:EGAS00001003171

The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Microarray raw data on Chronic Thromboembolic Pulmonary Hypertension (CTEPH) endothelial cells, and a healthy control patients group ega:EGAS00001008389

Microarray raw data on Chronic Thromboembolic Pulmonary Hypertension (CTEPH) endothelial cells, and a healthy control patients group

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Quantification of ω-3 fatty acids and their derivatives in lungs from hypoxia-induced pulmonary hypertension (PH) mice. metabolomics_workbench:ST001951

mouse METABOLOMICS

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.

NIH WCMC Pilot & Feasibility Project: Metabolomics of Neonatal Pulmonary Hypertension in human metabolomics_workbench:ST000255

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.

Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension massive:MSV000086005

Human endogenous retroviral (HERV) proteins are induced by exogenous viruses or other factors that derepress HERV transcription and translation. Previously we showed that HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins are increased in monocytes and macrophages from patients with pulmonary arterial hypertension (PAH). Recombinant HERV-K dUTPase upregulates IL6 in pulmonary arterial endothelial cells (PAECs) and induces pulmonary hypertension in rats.

Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.

{ }

Source YAML

click to show

name: Pulmonary_hypertension
creation_date: '2025-12-04T16:57:31Z'
description: >-
  Pulmonary hypertension is a hemodynamic disorder defined by abnormally elevated
  mean pulmonary arterial pressure. In pulmonary arterial hypertension,
  endothelial dysfunction and an imbalance of vasoactive mediators drive
  vasoconstriction and obstructive remodeling of the small pulmonary arteries
  (heritable forms involve BMPR2 and related TGF-beta pathway genes); other
  groups arise from left heart disease, lung disease, or chronic thromboembolism.
  Rising pulmonary vascular resistance imposes right ventricular overload,
  leading to right heart failure.
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
  prevalence_class: RARE
  percentage: Rare
progression:
- phase: Onset
  age_range: Variable, can occur at any age
  notes: Presentation depends on underlying cause
genetic:
- name: BMPR2
  gene_term:
    preferred_term: BMPR2
    term:
      id: hgnc:1078
      label: 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
  gene_term:
    preferred_term: SMAD9
    term:
      id: hgnc:6774
      label: SMAD9
  association: TGF-beta/BMP axis component implicated in PAH
  notes: Downstream transcription factor in BMP signaling pathway
- name: ACVRL1
  gene_term:
    preferred_term: ACVRL1
    term:
      id: hgnc:175
      label: 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
  gene_term:
    preferred_term: ENG
    term:
      id: hgnc:3349
      label: ENG
  association: Implicated in PAH
  notes: Encodes endoglin, a TGF-beta co-receptor involved in vascular development
- name: EIF2AK4
  gene_term:
    preferred_term: EIF2AK4
    term:
      id: hgnc:19687
      label: 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
  gene_term:
    preferred_term: KCNK3
    term:
      id: hgnc:6278
      label: 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
  gene_term:
    preferred_term: TBX4
    term:
      id: hgnc:11603
      label: TBX4
  association: Transcriptional regulator contributing to developmental and adult-onset PAH
  notes: Encodes T-box transcription factor 4
- name: SOX17
  gene_term:
    preferred_term: SOX17
    term:
      id: hgnc:18122
      label: SOX17
  association: Variants associated with severe PAH phenotype
  notes: Encodes SRY-box transcription factor 17; regulates vascular development
- name: CAV1
  gene_term:
    preferred_term: CAV1
    term:
      id: hgnc:1527
      label: 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.
  downstream:
  - target: Increased Pulmonary Vascular Resistance
    description: >-
      Medial hypertrophy, intimal proliferation, and fibrosis narrow and obliterate
      the small pulmonary arteries, which is the structural basis of the rise in
      pulmonary vascular resistance.
    causal_link_type: DIRECT
- 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.
  downstream:
  - target: Vascular Remodeling
    description: >-
      Endothelial injury, apoptosis, and endothelial-to-mesenchymal transition
      with loss of protective BMPR2 signaling initiate the proliferative
      remodeling of the small pulmonary arteries.
    causal_link_type: DIRECT
    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: Places endothelial dysfunction upstream as the initial trigger of the remodeling process this edge asserts.
  - target: Increased Pulmonary Vascular Resistance
    description: >-
      Loss of endothelial vasodilator output and excess vasoconstrictor mediators
      raise pulmonary arterial tone directly, before and alongside the structural
      remodeling.
    causal_link_type: DIRECT
- 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.
  downstream:
  - target: Vascular Remodeling
    description: >-
      Perivascular macrophage and lymphocyte infiltration with sustained cytokine
      release is what fuels the proliferative and fibrotic changes in the vessel
      wall.
    causal_link_type: DIRECT
- 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.
  downstream:
  - target: Vascular Remodeling
    description: >-
      The glycolytic shift sustains the proliferation and apoptosis resistance of
      pulmonary vascular smooth muscle and endothelial cells that build the
      remodeled vessel wall.
    causal_link_type: DIRECT
- 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
  downstream:
  - target: Increased Pulmonary Vascular Resistance
    description: >-
      Hypoxia constricts the pulmonary arterioles acutely, raising resistance
      before any structural change has occurred.
    causal_link_type: DIRECT
  - target: Vascular Remodeling
    description: >-
      Sustained HIF pathway activation drives the proliferative smooth-muscle and
      matrix changes that convert reversible hypoxic vasoconstriction into fixed
      remodeling.
    causal_link_type: DIRECT
- 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.
  downstream:
  - target: Right Ventricular Hypertrophy
    description: >-
      Elevated resistance raises the pressure the right ventricle must generate at
      every beat, and the ventricle hypertrophies in response to that afterload.
    causal_link_type: DIRECT
  - target: Dyspnea
    description: >-
      A pulmonary circulation that cannot accommodate an increase in flow caps the
      cardiac output achievable on exertion, which is experienced as
      breathlessness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- 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
  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.
  - target: Tricuspid Regurgitation
    description: >-
      As the pressure-loaded right ventricle dilates, the tricuspid annulus is
      distorted and the leaflets no longer coapt.
    causal_link_type: DIRECT
  - target: Edema
    description: >-
      Once the right ventricle decompensates, raised right-sided filling
      pressures are transmitted into the systemic venous bed and produce
      dependent oedema.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Fatigue
    description: >-
      A right ventricle that cannot deliver an adequate cardiac output limits
      systemic oxygen delivery, which patients report as persistent tiredness.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Syncope
    description: >-
      When the fixed pulmonary vascular resistance prevents any rise in cardiac
      output on exertion, cerebral perfusion falls and exertional syncope
      results.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Chest Pain
    description: >-
      The hypertrophied, high-pressure right ventricle outgrows its coronary
      supply, and the resulting subendocardial ischaemia presents as chest pain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Palpitations
    description: >-
      Right atrial and ventricular dilatation provides the substrate for the
      supraventricular arrhythmias that patients perceive as palpitations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cyanosis
    description: >-
      Low cardiac output with a widened arteriovenous oxygen difference, and in
      some patients right-to-left shunting through a patent foramen ovale,
      produce visible cyanosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
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
  readouts:
  - target: Right Ventricular Hypertrophy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >-
      Natriuretic peptide release tracks right ventricular wall stress, so the
      circulating level reports the load on the pressure-overloaded right
      ventricle rather than the pulmonary vascular lesion itself.
diagnosis:
- name: Echocardiogram
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  notes: Estimates pulmonary artery pressure and evaluates right heart function
- name: Right Heart Catheterization
  diagnosis_term:
    preferred_term: right heart catheterization
    term:
      id: NCIT:C38044
      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
  evidence:
  - reference: PMID:33578749
    reference_title: Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension."
    explanation: >-
      Names pulmonary hypertension as a cardio-pulmonary consequence of the
      alveolar hypoxia that defines the high-altitude environment, which is the
      association this exposure entry asserts.
  - reference: PMID:33578749
    reference_title: Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure."
    explanation: >-
      Gives the route from the exposure to the disease and on to right heart
      failure, distinguishing sustained exposure, which remodels the pulmonary
      vasculature, from the acute vasoconstrictive response.
  influences_mechanisms:
  - target: Hypoxia Signaling
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The alveolar hypoxia that defines the high-altitude environment is the
      stimulus that activates the HIF pathway and hypoxic pulmonary
      vasoconstriction.
    evidence:
    - reference: PMID:33578749
      reference_title: Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension."
      explanation: >-
        Names alveolar hypoxia as the operative feature of the high-altitude
        environment and pulmonary hypertension as its cardio-pulmonary
        consequence, which is the exposure-to-mechanism step asserted here.
  - target: Vascular Remodeling
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained rather than acute high-altitude exposure converts reversible
      hypoxic vasoconstriction into fixed remodeling of the pulmonary
      vasculature.
    evidence:
    - reference: PMID:33578749
      reference_title: Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure."
      explanation: >-
        States that chronic hypoxic exposure induces pulmonary vascular
        remodeling, which is exactly the exposure-to-mechanism link on this edge.
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.
  target_mechanisms:
  - target: Increased Pulmonary Vascular Resistance
    treatment_effect: INHIBITS
    description: >-
      Blocking cGMP breakdown in pulmonary vascular smooth muscle sustains
      nitric-oxide-mediated vasodilation and lowers pulmonary vascular
      resistance.
- 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
  target_mechanisms:
  - target: Increased Pulmonary Vascular Resistance
    treatment_effect: INHIBITS
    description: >-
      Endothelin receptor blockade removes one arm of the vasoactive mediator
      imbalance produced by the dysfunctional endothelium, lowering pulmonary
      arterial tone.
  - target: Endothelial Dysfunction
    treatment_effect: MODULATES
    description: >-
      The drug acts on the consequences of endothelial mediator imbalance rather
      than repairing the endothelium, so it modulates this node rather than
      restoring it.
- 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
  target_mechanisms:
  - target: Increased Pulmonary Vascular Resistance
    treatment_effect: INHIBITS
    description: >-
      Replacing the prostacyclin the dysfunctional endothelium no longer makes
      dilates the pulmonary arterial bed and lowers resistance.
- 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
      term:
        id: NCIT:C80038
        label: 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.
  target_mechanisms:
  - target: Vascular Remodeling
    treatment_effect: INHIBITS
    description: >-
      Sotatercept is an activin-signaling ligand trap; rebalancing pro-growth
      activin against protective BMP signaling targets the proliferative
      remodeling itself rather than pulmonary arterial tone.
- name: Oxygen Therapy
  description: Used to reduce symptoms in patients with hypoxemia
  treatment_term:
    preferred_term: Oxygen Therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  target_mechanisms:
  - target: Hypoxia Signaling
    treatment_effect: INHIBITS
    description: >-
      Raising alveolar oxygen tension removes the hypoxic stimulus for HIF
      pathway activation and hypoxic pulmonary vasoconstriction.
  - target: Cyanosis
    treatment_effect: INHIBITS
    description: >-
      Supplemental oxygen raises arterial saturation, which is the symptomatic
      benefit in hypoxaemic patients.
- name: Anticoagulation
  description: Used particularly in chronic thromboembolic pulmonary hypertension to prevent clotting complications
  target_mechanisms:
  - target: Increased Pulmonary Vascular Resistance
    treatment_effect: INHIBITS
    description: >-
      In chronic thromboembolic pulmonary hypertension anticoagulation prevents
      further thromboembolic obstruction from adding to the fixed resistance;
      it does not act on the vasoconstrictive or remodeling mechanisms this
      entry otherwise models, and this entry carries no thromboembolic
      obstruction node for it to target directly.
  treatment_term:
    preferred_term: cardiovascular agent therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
- name: Balloon Pulmonary Angioplasty
  description: >
    Catheter-based interventional treatment for chronic thromboembolic pulmonary
    hypertension (CTEPH), particularly in patients with inoperable or
    distal-vessel disease or persistent pulmonary hypertension after pulmonary
    endarterectomy. Serial balloon dilation of stenotic/occluded pulmonary
    arteries reduces pulmonary vascular resistance and improves functional
    capacity.
  treatment_term:
    preferred_term: balloon pulmonary angioplasty
    term:
      id: NCIT:C217465
      label: Percutaneous Transluminal Angioplasty
  evidence:
  - reference: PMID:42055655
    reference_title: "Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension: Statement From the BPA-CTEPH Alliance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Balloon pulmonary angioplasty (BPA) has emerged as a very effective therapeutic option in these patients."
    explanation: The BPA-CTEPH Alliance statement establishes balloon pulmonary angioplasty as an effective therapeutic option for chronic thromboembolic pulmonary hypertension.
  - reference: PMID:42055655
    reference_title: "Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension: Statement From the BPA-CTEPH Alliance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life."
    explanation: Quantifies the hemodynamic and functional benefit of BPA in CTEPH.
  target_mechanisms:
  - target: Increased Pulmonary Vascular Resistance
    treatment_effect: INHIBITS
    description: >-
      Serial balloon dilation reopens stenotic and occluded pulmonary arteries in
      chronic thromboembolic disease, mechanically lowering the fixed component
      of pulmonary vascular resistance.
    evidence:
    - reference: PMID:42055655
      reference_title: "Balloon Pulmonary Angioplasty for Treatment of Chronic Thromboembolic Pulmonary Hypertension: Statement From the BPA-CTEPH Alliance."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Contemporary evidence suggests that BPA is associated with significant improvements in pulmonary vascular resistance, mean pulmonary artery pressure, functional class, and quality of life."
      explanation: Reports improvement in pulmonary vascular resistance itself, which is the node this treatment link targets.
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: []
datasets:
- accession: geo:GSE126322
  title: Remodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension [ChIP-seq]
  description: Pulmonary Arterial Hypertension (PAH) is a cardiovascular disease characterized by progressively increasing blood pressure as a result of obliteration and loss of pulmonary arteries. We have extracted pulmonary arterial endothelial cells from lungs of a cohort of PAH patients (n=10) and controls (n=9), cultured the cells for 3-5 passages, and performed chromatin (H3K27ac, H3K4me1, and H3K4me3 ChIP-Seq), expression (RNA-Seq) and chromatin interaction profiling (ChIA-PET). We observed a large-scale remodelling of the active chromatin landscape at enhancers while promoters and gene expression remained unchanged.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: CHIP_SEQ
  sample_count: 55
  publication: PMID:32245974
  notes: Identified by GEO DataSets index search for Pulmonary hypertension (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE314466
  title: Global knockout of melanoma differentiation-associated protein 5 protects mice from chronic hypoxia/SU5416-induced pulmonary hypertension
  description: Pulmonary arterial hypertension (PAH) is a severe disease affecting the pulmonary arteries, causing increased blood pressure due to narrowing of the pulmonary artery lumen. Aberrant proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs), along with a dysregulation of the immune response, contributes to arterial remodeling. We hypothesized that the cytosolic RNA receptor melanoma differentiation-associated protein 5 (MDA5) contributes to PAH by dysregulating pulmonary vascular cell function and immune cell response. In lung tissue from control patients and PAH patients, MDA5 immunoreactivity was widely distributed throughout the pulmonary artery wall.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:42030239
  notes: Identified by GEO DataSets index search for Pulmonary hypertension (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001003155
  title: High Altitude Pulmonary Hypertension
  description: The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WGS
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001003171
  title: High Altitude Pulmonary Hypertension
  description: The Central Asian Kyrgyz highland population provides a unique opportunity to address genetic diversity and understand the genetic mechanisms underlying hypoxia-induced high altitude pulmonary hypertension (HAPH). While a significant fraction of the population is unaffected, there are susceptible individuals who display HAPH in the absence of any lung, cardiac or hematologic disease. We report herein the analysis of the whole genome sequencing of healthy individuals compared with HAPH patients and other controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001008389
  title: Microarray raw data on Chronic Thromboembolic Pulmonary Hypertension (CTEPH) endothelial cells, and a healthy control patients group
  description: Microarray raw data on Chronic Thromboembolic Pulmonary Hypertension (CTEPH) endothelial cells, and a healthy control patients group
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Pulmonary hypertension"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST001951
  title: Quantification of ω-3 fatty acids and their derivatives in lungs from hypoxia-induced pulmonary hypertension (PH) mice.
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST000255
  title: "NIH WCMC Pilot & Feasibility Project:  \x93Metabolomics of Neonatal Pulmonary Hypertension\x94 in human"
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.
- accession: massive:MSV000086005
  title: Monocytes Release Endogenous Retroviral Protein in Exosomes Causing  a Mesenchymal, Proinflammatory Endothelium  and Pulmonary Hypertension
  description: Human endogenous retroviral (HERV) proteins are induced by exogenous viruses or other factors that derepress HERV transcription and translation. Previously we showed that HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins are increased in monocytes and macrophages from patients with pulmonary arterial hypertension (PAH). Recombinant HERV-K dUTPase upregulates IL6 in pulmonary arterial endothelial cells (PAECs) and induces pulmonary hypertension in rats.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Pulmonary hypertension"). Retrieved 2026-08-02.

📚

References & Deep Research

References

4

DOI:10.1038/s41392-025-02287-8

Signaling pathways and targeted therapy for pulmonary hypertension

No top-level findings curated for this source.

DOI:10.1038/s41598-024-64251-w

Transcriptomic profiling highlights cell proliferation in the progression of experimental pulmonary hypertension in rats

No top-level findings curated for this source.

DOI:10.1164/rccm.202302-0327so

Pulmonary Hypertension: A Contemporary Review

No top-level findings curated for this source.

DOI:10.31083/j.rcm2506217

Roles of LncRNAs in the Pathogenesis of Pulmonary Hypertension

No top-level findings curated for this source.

Deep Research

2

Disorder ▸

Disorder

Name: Pulmonary_hypertension
Category: Cardiovascular Disorder
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 5

Key Pathophysiology Nodes

Vascular Remodeling
Endothelial Dysfunction
Inflammation and Immune Activation
Metabolic Reprogramming
Hypoxia Signaling
Increased Pulmonary Vascular Resistance
Right Ventricular Hypertrophy
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1038/s41392-025-02287-8
DOI:10.1038/s41598-024-64251-w
DOI:10.1164/rccm.202302-0327so
DOI:10.31083/j.rcm2506217

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 15 citations 2025-12-14T23:45:00.601504

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.

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