The Role of Ion Channels in Pulmonary Hypertension: A Review

The history of advances in understanding pulmonary circulation is long, dating to the 13th century. Subsequent centuries produced halting progress until the 20th century when investigators applied right heart catheterization and light-microscopy to better understand the physiology and pathology of pulmonary hypertension (PH). The work of Paul Wood, Cornelis Wagenvoort, and others during the first seven decades of the 20th century set the stage for five decades of extraordinary progress.

Transcription factor TBX4 rare variants associate with pulmonary arterial hypertension (PAH), particularly in children, and are the second most common cause of heritable PAH. However, TBX4's down-stream targets and the molecular and cellular pathways these targets regulate remain largely unknown in PAH. 

Female sex increases risk of Group I pulmonary arterial hypertension by roughly threefold, but the mechanism is unclear. Low expression of Cyp1b1, an enzyme that metabolizes estrogens, is associated with disease penetrance, particularly in women. We previously found that lower Pparγ levels in murine PAH models, which may drive disease, are rescued by estrogen blockade.

Pulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools.