TABLE 14

Pulmonary arterial hypertension (PAH): a review from the literature of the different multi-model combination systems used to study a specific aspect of pulmonary hypertension (PH) pathogenesis

Area of researchMain focusMain experimental tools usedReferences
Genetic factorsGenetic studiesGenomic DNA sample and/or microdissected cell DNA and matching clinical features of discovery and validation cohorts
Genome/exome seq and functional studies
[S447–S453]
Induced pluripotent stem cells (iPSCs) combined with next generation sequencing[S454, S455]
Related review: [S456]
Role of a specific gene mutation: i.e. BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV, TBX4, NOTCH3 or KCNK3 mutationGenomic DNA sample and/or microdissected cell DNA and matching clinical data
DNA-Seq, RNA-Seq, functional studies
[S447, S449, S451, S453, S457–S477]
EpigeneticMethyl-Seq, and/or methyl-DNA immune precipitation chips
In vivo models in rodents and/or in vitro cell culture models
[S478–S493]
PolymorphismsDNA sample with matching clinical data and functional studies[S494–S544]
Environmental factorsHypoxia (acute, chronic or intermittent hypoxia exposure)In vivo model(s) in rodents and larger mammals, and/or in vitro cell culture models, and/or analyses of human samples from patients from the group 3 of the current clinical classification of PH and/or human samples from healthy subjects or patients exposed to high altitudeSelection of related reviews: [S545–S648]
Drugs and toxinsIn vivo model(s) in rodents and larger mammals, and/or in vitro cell culture models, and/or pharmacovigilance programmeSelection of related reviews: [S649–S675]
Lifestyle factors (nutrition, tobacco use, physical activity, etc.)In vivo model(s) in rodents and/or larger mammals, and/or epidemiological studySelection of related reviews: [S673, S676–S716]
Infectious agentsIn vivo model(s) in rodents (schistosomiasis) and larger mammals, and/or in vitro cell culture modelsSelection of related reviews: [S712, S717–S755]
Pulmonary endothelial dysfunctionProduction of vasoreactive mediators
Phenotypic alterations of pulmonary endothelial cells: enhanced proliferation, resistance to apoptosis and pro-inflammatory state
Production of activators and inhibitors of smooth muscle cell growth and migration
Production of prothrombotic and antithrombotic mediators
Production of proinflammatory signals
Barrier function
Regulation of endothelial cell differentiation and specification
In vivo model(s) in rodents (MCT model, Su5416+hypoxia models or aortic banding model) and/or larger mammals
In vitro cell culture models
Analyses of human samples
Su5416+hypoxia model and in vitro cell culture models
MCT model, BMPR2 deficient animals
Endothelial-targeted, fas-induced apoptosis (FIA) transgenic mice
Selection of related reviews: [S663, S756–S818]
Smooth muscle hyperplasiaBalance between proliferation and apoptosis
Properties of smooth muscle hyperpolarisation and relaxation
Deregulations of cellular energetics
Smooth muscle cell differentiation
Ion channels and membrane potential
In vivo model(s) in rodents and larger mammals, and/or in vitro cell culture models
Analyses of human samples from PAH patients and/or human samples from healthy subjects or patients exposed to high altitude
MCT model, BMPR2 deficient animals
Selection of related reviews: [S584, S590, S761, S775, S791, S794, S802, S819–851]
Plexogenic pulmonary vascular lesionsHistological analyses
Endothelial cell proliferation and apoptosis
Analyses of human samples from PAH patients
Su5416+hypoxia hypoxia model, Su5416+ pneumonectomy model
[S475, S852–S863]
Adventitial fibrosisPhenotypic alterations of adventitial fibroblasts: enhanced proliferation, resistance to apoptosis and pro-inflammatory and profibrotic states
Secretion of mediators
In vivo model(s) in rodents and larger mammals, and/or in vitro cell culture models
Analyses of human samples from PAH patients and/or human samples from healthy subjects or patients exposed to high altitude
Selection of related reviews: [S556, S589, S599, S617, S783, S864–869]
Metabolism dysregulationShift from glycolytic to oxidative metabolism
Mitochondrial alterations
Fatty acid metabolism
Analyses of human samples from PAH patients and/or human samples from healthy subjects and/or in vivo imaging
In vivo model(s) in rodents and larger mammals, and/or in vitro cell culture models
Selection of related reviews: [S556, S840, S870–S874]
In situ thrombosisBlood coagulation and fibrinolysis
Platelet biology
Histological analyses
Analyses of human samples from PAH patients and/or human samples from healthy subjects
In vivo model(s) in rodents and larger mammals
Selection of related reviews: [S765, S875–S892]
Inflammation and dysimmunityCytokine/chemokine secretion and roles
Immune cell infiltration
Autoimmunity
Lymphoid neogenesis
Rat models of MCT, mouse models of chronic hypoxia
Rat models of MCT, Su5416+hypoxia, Su-ovalbumin, or aortic banding
Rat models of MCT, Su5416+hypoxia, Su5416+ovalbumin
Rat models of MCT, Su5416+hypoxia, Su5416+ovalbumin
Selection of related reviews: [S558, S617, S620, S758, S763, S766, S775, S893–S923]

For references listed in the table please refer to the supplementary material.