Pathobiology of pulmonary arterial hypertension: understanding the roads less travelled

Abstract

The pathobiology of pulmonary arterial hypertension (PAH) is complex and incompletely understood. Although three pathogenic pathways have been relatively well characterised, it is widely accepted that dysfunction in a multitude of other cellular processes is likely to play a critical role in driving the development of PAH. Currently available therapies, which all target one of the three well-characterised pathways, provide significant benefits for patients; however, PAH remains a progressive and ultimately fatal disease. The development of drugs to target alternative pathogenic pathways is, therefore, an attractive proposition and one that may complement existing treatment regimens to improve outcomes for patients. Considerable research has been undertaken to identify the role of the less well-understood pathways and in this review we will highlight some of the key discoveries and the potential for utility as therapeutic targets.

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.