Molecular Signaling in Pulmonary Vein Stenosis: Toward Lesion-Specific Phenotyping and Individualized Therapy

Pulmonary vein stenosis (PVS) is a rare but life-threatening disease affecting young children, characterized by progressive narrowing of the pulmonary veins. Multimodal treatment, including surgical and catheter-based interventions combined with medical therapy, can improve survival; however, disease recurrence and progression are common. Currently, there is no therapy able to reverse existing disease, leaving lung transplantation the only option for patients with advanced, treatment-resistant disease. Studies using animal models and human tissue have identified several mechanisms that contribute to PVS, including mechanosensitive signaling and endothelial-to-mesenchymal transition. In parallel, advances in cardiac imaging and hemodynamic profiling of individual pulmonary veins have improved risk stratification and provided opportunities to modify treatment strategies. Despite these advances, the development of disease-modifying therapies able to improve patient outcomes will require a more thorough understanding of the underlying pathophysiology. In this review, we examine the histological features of PVS and summarize the cellular contributions and signaling pathways implicated in disease development. We will also explore the potential of integrating patient- and lesion-specific phenotypes and molecular signatures to guide individual treatment strategies, as well as the current limitations and future directions of PVS research.