Therapeutic Targets for Pediatric Pulmonary Vein Stenosis: Insights from Animal Models

Pulmonary vein stenosis (PVS) is a rare and devastating condition affecting infants and children, characterized by progressive intimal hyperplasia, myofibroblast proliferation, and extracellular matrix deposition, leading to pulmonary hypertension and right heart failure. Despite multimodal interventions including surgery and catheter-based approaches, long-term outcomes remain poor due to high rates of restenosis and disease progression. The development of representative animal models has been instrumental in unraveling the complex pathophysiology of PVS and identifying potential therapeutic targets. This review comprehensively examines the evolution of PVS animal models—from large animals to recently established rodent models—and synthesizes insights gained regarding key pathogenic pathways and their therapeutic implications and guiding associated clinical trials in pediatric patients. We discuss evidence supporting mammalian target of rapamycin (mTOR) inhibition, renin-angiotensin system blockade, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) targeting, and emerging strategies including fibroblast activation protein (FAP) inhibition and YAP/β-catenin pathway modulation. The recent development of neonatal rat PVS models has accelerated translational research by enabling cost-effective, high-throughput evaluation of candidate therapies. We propose a mechanistic framework integrating these pathways and discuss future directions for precision medicine approaches in PVS.