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 resistance | HMGA1 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 SMCs | FGF-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 mutations | BMPR-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 apoptosis | CD20 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 PAH | KCNK3 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 models | miR-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.