Epigenetic mechanisms in pulmonary arterial hypertension: the need for global perspectives

Epigenetic mechanisms in pulmonary arterial hypertension (PAH). Genetic predisposition, age, sex, environmental factors and pathological stimuli such as hypoxia, shear stress, oxidative stress, infection, mitogens and inflammation (cytokines and chemokines) cause vascular injury. Endothelial dysfunction causes an imbalance in the production of several vasoactive substances thereby facilitating vasoconstriction. Activation of downstream signalling cascades arbitrates PAH progression via recruitment and modulation of transcription factors that regulate stimulus-specific transcriptional responses. Following the persistence of pathological stimuli, the gene regulatory signatures in the normal vascular cells are altered and thereby establish a phenotypic memory in PAH vascular cells. Aside from the hypoxia-induced metabolic shift, acquisition of epigenetic alterations consequently facilitates stimulus-independent aberrant transcription of pro-proliferative, pro-migratory, anti-apoptotic, pro-inflammatory and pro-fibrotic genes that underlie the different vascular cell phenotypes in PAH vasculature. Phenotypic switching of pulmonary vascular cells largely contributes to the development of complex vascular lesions during the progressive vascular remodelling process in PAH. ECM: extracellular matrix.