Sildenafil in bronchopulmonary dysplasia-associated pulmonary hypertension: developmental and translational insights

Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) is increasingly viewed as a developmental pulmonary vascular disorder rather than a purely reactive vasoconstrictive complication of chronic lung disease. It involves impaired angiogenesis, reduced pulmonary vascular surface area, alveolar simplification, and progressive right ventricle-pulmonary artery uncoupling. Sildenafil, a phosphodiesterase type 5 inhibitor, is widely used because it enhances nitric oxide-cyclic guanosine monophosphate signaling and may reduce pulmonary vascular tone. However, neonatal-specific evidence remains limited, dosing approaches are heterogeneous, and its long-term effects on vascular remodeling and clinical outcomes are uncertain. This narrative review integrates developmental biology, translational evidence, clinical studies, pharmacokinetics, and safety considerations to critically evaluate sildenafil in BPD-PH. Current data support short-term improvements in echocardiographic hemodynamics and oxygenation in selected infants, but do not demonstrate durable remodeling reversal or improved survival. Experimental studies suggest effects on endothelial survival, smooth muscle proliferation, angiogenic signaling, and oxidative stress, although relevance to human preterm infants remains incompletely validated. Developmental pharmacokinetics, including CYP3A maturation, weight, postnatal age, route, and drug interactions, contribute to variable exposure. Sildenafil use should therefore be individualized, phenotype-guided, and evaluated in future trials with pharmacokinetic-guided dosing and longitudinal outcomes. IMPACT: Reframes bronchopulmonary dysplasia-associated pulmonary hypertension as a disorder of impaired pulmonary vascular development rather than a purely reactive vasoconstrictive process. Integrates developmental biology, translational evidence, and neonatal pharmacokinetics to critically evaluate sildenafil beyond its traditional vasodilatory role. Highlights the need for precision pharmacology approaches and pharmacokinetic-guided dosing to optimize therapeutic strategies in preterm infants.