Molecular mechanisms of EPAS1 in regulating pulmonary vascular remodeling in COPD: a review

Chronic obstructive pulmonary disease (COPD) is an incompletely reversible heterogeneous lung disease with high morbidity and mortality. Progressive worsening of dyspnea is its core clinical manifestation, and patients often develop severe complications such as pulmonary hypertension during the advanced stages of the disease. The oxygen-sensitive gene endothelial PAS domain-containing protein 1 (EPAS1) is a core transcription factor activated under hypoxic conditions. EPAS1 acts as a key regulator of hypoxia-induced pulmonary vascular remodeling in COPD, although other hypoxia-responsive factors, including HIF-1α and NF-κB, also contribute to this complex process. This gene is involved in the pathological progression of COPD and is closely associated with pulmonary vascular remodeling. Pulmonary vascular remodeling, in turn, is a critical process in COPD pathogenesis, driven by chronic hypoxia, inflammatory responses, tobacco exposure, and cytokine dysregulation. These pathological changes can directly lead to the development of pulmonary hypertension and further exacerbate dyspnea symptoms. Under hypoxic conditions, aberrant expression of EPAS1 regulates the transcriptional activation of its target gene, vascular endothelial growth factor (VEGF), while also mediating the activation of the mitogen-activated protein kinase (MAPK) signaling pathway. These molecular events are closely related to the structural remodeling of pulmonary vasculature in COPD patients. Therefore, in-depth investigation into the molecular mechanisms by which EPAS1 regulates pulmonary vascular remodeling in the hypoxic microenvironment will not only help elucidate the pathogenesis of complications in advanced COPD but also provide potential molecular targets for clinical intervention, offering significant theoretical and clinical value for the precision treatment of COPD.