Figures
- 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
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
- TABLE 1
Pathogenic pathways and potential therapeutic targets in pulmonary arterial hypertension (PAH)
Pathway Role in PAH Potential therapeutic targets Refs Vascular stiffness Can activate the YAP/TAZ co-transcription factors, leading to further ECM remodelling and modulation of metabolic pathways Glutaminase
YAP/TAZ[9, 10] Endothelial-to-mesenchymal transition Can 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 resistanceHMGA1
TGF-β
BMPR-II[11–18] Pericyte-mediated vascular remodelling Increased 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 SMCsFGF-2
IL-6
TGF-β[19, 20] TGF-β signalling Loss 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 mutationsBMPR-II
TNF-α
SMURF 1
miR-140-5p[21–32] PDGF and FGF signalling Over-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 dysfunction FGF-2
PDGF[33–44] Inflammation and immunity Inflammatory mediators and cell infiltrates are frequently observed in PAH
Vascular cells can respond to inflammatory stimuli by enhanced proliferation and migration and reduced apoptosisCD20 B
IL-1β and IL-6
TNF-α[45–58] Resting membrane potential Loss-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 PAHKCNK3
Kv1.5[59–67] Oestrogen signalling E2 metabolites can exert both detrimental and protective effects in
PAH
E2 may directly protect against the development of PH in animal
modelsmiR-29
E2 metabolites[68–75] Iron homeostasis Iron deficiency may play a role in pulmonary vascular remodelling Iron 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)
Pathway Role in PAH Potential therapeutic targets Refs Transcription factors FoxO1, 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 PAHFoxO1
STAT3/PIM1
NFAT, HIF-1α[28, 82, 83] NOTCH3-HES5 signalling NOTCH3 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 PAHNOTCH3-HES5 pathway [84] Epigenetic mechanisms Methylation-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 PAHSOD2
HDACs
BRD4
miRNAs[85–88] DNA damage/
PARP-1 signalling pathwayActivation 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 PAHDNA damage/PARP-1 signalling pathway [82, 89] VEGFR signalling VEGF 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 clearVEGFR 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.
