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Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Anna R. Hemnes, Marc Humbert
European Respiratory Review 2017 26: 170093; DOI: 10.1183/16000617.0093-2017
Anna R. Hemnes
1Dept of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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  • For correspondence: anna.r.hemnes@vanderbilt.edu
Marc Humbert
2Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
3AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
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  • FIGURE 1
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    FIGURE 1

    A genetic predisposition combined with environmental risk factors may be involved in the development of pulmonary arterial hypertension (PAH). In individuals without mutations in PAH-associated genes (genetically non-susceptible), epigenetic changes and exposure to environmental triggers over time can result in progressive pulmonary vascular dysfunction. This process is accelerated in individuals carrying mutations in PAH-associated genes (genetically susceptible). Reproduced and modified from [8] with permission from the publisher.

  • FIGURE 2
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    FIGURE 2

    Diverse cellular processes and signalling pathways contribute to the pathogenesis of pulmonary arterial hypertension (PAH). Dysfunction in a myriad of overlapping signalling pathways can promote endothelial cell (EC) proliferation and differentiation, smooth muscle cell (SMC) proliferation, migration and vasoconstriction, pericyte proliferation, migration and differentiation, endothelial-to-mesenchymal transition, immune cell infiltration and extracellular matrix (ECM) remodelling in the pulmonary artery. This figure illustrates the pathways and processes discussed in this article and is not an exhaustive illustration of all the pathways currently understood to be involved in the pathogenesis of PAH. EndMT: endothelial-to-mesenchymal transition; TGF-β: transforming growth factor- β; TGF-βR: TGF-β receptor; BMP: bone morphogenetic protein; BMPR-II: BMP receptor type 2; IL-6: interleukin-6; IL-6R: IL-6 receptor; FGF-2: fibroblast growth factor-2; FGFR: FGF receptor; PDGF: platelet-derived growth factor; PDGFR: PDGF receptor; E2: oestradiol; ER: oestrogen receptor; YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif; 16αOHE: 16α-hydroxyoestrone; 2-OHE2: 2-hydroxyoestradiol; 2-ME2: 2-methoxyoestradiol; miR130/301: microRNA-130/301 family.

Tables

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  • TABLE 1

    Pathogenic pathways and potential therapeutic targets in pulmonary arterial hypertension (PAH)

    PathwayRole in PAHPotential therapeutic targetsRefs
    Vascular stiffnessCan activate the YAP/TAZ co-transcription factors, leading to further ECM remodelling and modulation of metabolic pathwaysGlutaminase
    YAP/TAZ
    [9, 10]
    Endothelial-to-mesenchymal transitionCan be induced by haemodynamic changes associated with PAH
    TGF-β signalling and HMGA1 may play a role in EndMT
    EndMT cells can migrate, remodel the ECM and have increased apoptosis resistance
    HMGA1
    TGF-β
    BMPR-II
    [11–18]
    Pericyte-mediated vascular remodellingIncreased pericyte density in distal pulmonary arteries has been reported in PAH
    FGF-2 and IL-6 can stimulate pericyte migration and proliferation
    TGF-β can promote the differentiation of pericytes into SMCs
    FGF-2
    IL-6
    TGF-β
    [19, 20]
    TGF-β signallingLoss of function heterozygous BMPR2 mutations have been reported in PAH
    In the absence of a mutation, BMPR-II expression is frequently reduced in PAH
    Suppression of BMPR-II signalling leads to increased proliferation and decreased apoptosis in vascular cells
    Inflammatory mediators, e.g. TNF-α, may play a role in PAH pathogenesis in the context of BMPR2 mutations
    BMPR-II
    TNF-α
    SMURF 1
    miR-140-5p
    [21–32]
    PDGF and FGF signallingOver-expression of PDGF and FGF has been reported in PAH and may be involved in abnormal proliferation and migration of SMCs, as well as endothelial dysfunctionFGF-2
    PDGF
    [33–44]
    Inflammation and immunityInflammatory mediators and cell infiltrates are frequently observed in PAH
    Vascular cells can respond to inflammatory stimuli by enhanced proliferation and migration and reduced apoptosis
    CD20 B
    IL-1β and IL-6
    TNF-α
    [45–58]
    Resting membrane potentialLoss-of-function KCNK3 mutations have been reported in PAH
    May contribute to pulmonary vasoconstriction and pulmonary vascular remodelling
    Expression of the Kv1.5 channel is also reduced in human and experimental PAH
    KCNK3
    Kv1.5
    [59–67]
    Oestrogen signallingE2 metabolites can exert both detrimental and protective effects in
    PAH
    E2 may directly protect against the development of PH in animal
    models
    miR-29
    E2 metabolites
    [68–75]
    Iron homeostasisIron deficiency may play a role in pulmonary vascular remodellingIron replacement[76–81]

    TGF-β: transforming growth factor-β; PDGF: platelet-derived growth factor; FGF: fibroblast growth factor; YAP: Yes-associated protein; TAZ: transcriptional coactivator with PDZ-binding motif; ECM: extracellular matrix; HMGA1: High Mobility Group AT-Hook 1; EndMT: endothelial-to-mesenchymal transition; BMPR-II: bone morphogenic protein receptor type 2; IL: interleukin; SMC: smooth muscle cell; TNF-α: tumour necrosis factor-α; SMURF: SMAD-specific E3 ubiquitin protein ligase; miR: microRNA; CD20 B: cluster of differentiation 20 B-lymphocyte antigen; KCNK3: potassium channel subfamily K member 3; Kv1.5: voltage-dependent potassium channel 1.5; E2: oestradiol; PH: pulmonary hypertension.

    • TABLE 2

      Additional pathogenic pathways and potential therapeutic targets in pulmonary arterial hypertension (PAH)

      PathwayRole in PAHPotential therapeutic targetsRefs
      Transcription factorsFoxO1, a member of the Forkhead box O (FoxO) family of transcription factors that are key regulators of cellular proliferation, is downregulated in pulmonary vessels/PASMCs of human/experimental PH lungs
      Activation of the prosurvival transcription factors STAT3, NFAT, and HIF-1α has been demonstrated in experimental models of PAH
      FoxO1
      STAT3/PIM1
      NFAT, HIF-1α
      [28, 82, 83]
      NOTCH3-HES5 signallingNOTCH3 is overexpressed in small PASMCs in human PH
      There is evidence for a link between NOTCH3 receptor signalling through HES5 and SMC proliferation in the development of PAH
      NOTCH3-HES5 pathway[84]
      Epigenetic mechanismsMethylation-induced downregulation of SOD2 in PASMCs may create a metabolic state that favours proliferation and suppresses apoptosis
      Aberrant expression of HDACs and BRD4 (a transcriptional regulator that recognises acetylated lysine residues) is consistent with altered epigenetic mechanisms in PAH
      Studies have shown that miRNAs (small RNA molecules that negatively regulate expression of target genes) are dysregulated in patients with PAH
      SOD2
      HDACs
      BRD4
      miRNAs
      [85–88]
      DNA damage/
      PARP-1 signalling pathway
      Activation of PARP-1 (a DNA repair enzyme) may lead to subsequent activation of transcription factors (NFAT, HIF-1α) that are implicated in PAH
      Inflammation induces DNA damage in PASMCs (levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells), which may lead to activation of PARP-1 in PAH
      DNA damage/PARP-1 signalling pathway[82, 89]
      VEGFR signallingVEGF plasma levels are elevated in patients with severe PAH, and expression of VEGF and VEGFR2 is robust in complex vascular lesions of PAH lungs
      Role of VEGF in mechanisms of PAH development is not clear
      VEGFR signalling[90]

      HES5: hairy and enhancer of split 5; PARP-1: Poly [ADP-ribose] polymerase 1; VEGFR: vascular endothelial growth factor receptor; PASMCs: pulmonary artery smooth muscle cells; PH: pulmonary hypertension; STAT3: Signal transducer and activator of transcription 3; NFAT: nuclear factor of activated T-cells; HIF-1α: hypoxia-inducible factor-1α; PIM1: proto-oncogene serine/threonine-protein kinase; SMC: smooth muscle cell; SOD2: superoxide dismutase 2; HDACs: histone deacetylases; BRD4: bromodomain-containing protein 4; miRNAs: microRNAs; VEGF: vascular endothelial growth factor.

      Supplementary Materials

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        A.R. Hemnes ERR-0093-2017_Hemnes

        M. Humbert ERR-0093-2017_Humbert

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      Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled
      Anna R. Hemnes, Marc Humbert
      European Respiratory Review Dec 2017, 26 (146) 170093; DOI: 10.1183/16000617.0093-2017

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      Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled
      Anna R. Hemnes, Marc Humbert
      European Respiratory Review Dec 2017, 26 (146) 170093; DOI: 10.1183/16000617.0093-2017
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      • Article
        • Abstract
        • Abstract
        • Introduction
        • Vascular stiffness
        • Endothelial-to-mesenchymal transition
        • Pericyte-mediated vascular remodelling
        • Growth factor signalling
        • Inflammation and immunity
        • Resting membrane potential
        • Oestrogen signalling
        • Iron homeostasis
        • Conclusions
        • Disclosures
        • Acknowledgements
        • Footnotes
        • References
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      • Mechanisms of lung disease
      • Pulmonary vascular disease
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