Translational Potential of Hypoxia-Inducible Factor-2α Signaling in Pulmonary Hypertension

Pulmonary hypertension (PH) is a life-threatening condition characterized by elevated blood pressure in the pulmonary arteries, leading to right heart failure. The hypoxia-inducible factor (HIF)-2α has been shown to play a critical role in PH development. Studies in humans and animals have provided genetic evidence linking HIF-2α signaling to PH. Tibetans and Andeans, who have adapted to high-altitude hypoxia, exhibit genetic variants in the EPAS1 gene, which encodes HIF-2α, conferring protection against PH. Furthermore, HIF-2α gain-of-function mutations have been identified in patients with severe PH. Animal models with genetic modifications in HIF-2α pathway genes have demonstrated the crucial role of HIF-2α in the pathogenesis of PH. HIF-2α signaling in pulmonary vascular endothelial cells has been implicated in regulating vasoconstriction and pulmonary vascular remodeling. Understanding the molecular and cellular mechanisms of HIF-2α in PH development may provide insights into potential therapeutic targets for PH.