Hypoxia-induced platelet activation and pulmonary platelets are increased in a murine model of neonatal chronic lung disease and pulmonary hypertension

Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) is a major cause of morbidity and mortality in preterm infants, yet available therapies lack mechanistic diversity and can be ineffective, highlighting an urgent need for novel therapeutic targets. Platelets are increasingly recognized as immune cells capable of driving pulmonary vascular inflammation, but their role in neonatal PH remains undefined. Neonatal mice were exposed to 12% hypoxia beginning at 12–24 h of life until postnatal day 8 (P8) or 15 (P15). Cardiopulmonary phenotype and markers of platelet activation were quantified using histology, flow cytometry, ELISA, and immunohistochemistry. Hypoxia produced a BPD-PH phenotype, including alveolar simplification, pulmonary vessel muscularization, elevated right ventricular systolic pressure, and right ventricular hypertrophy. Hypoxia disrupted the postnatal decline in pulmonary platelets and the platelet α-granule stored protein, platelet factor 4, resulting in increased pulmonary platelet accumulation at P15. Circulating platelets from hypoxic mice demonstrated increased activation, with higher P-selectin and activated αIIbβ3 expression at P8 and P15, enhanced agonist-induced P-selectin expression at P8, and increased leukocyte-platelet aggregation at P8. Postnatal hypoxia induces a robust, biologically meaningful platelet activation phenotype, supporting a previously unrecognized association between platelet activation and BPD-PH and identifying platelet activation pathways as potential therapeutic targets warranting further mechanistic investigation. Postnatal hypoxia drives persistent pulmonary platelet accumulation in a neonatal model of bronchopulmonary dysplasia-associated pulmonary hypertension. Hypoxic neonatal platelets exhibit increased P-selectin expression and αIIbβ3 activation, enhanced agonist responsiveness, and early leukocyte-platelet aggregation, indicating a shift toward a pro-inflammatory phenotype. These findings demonstrate that, despite developmental hyporesponsiveness, neonatal platelets are dynamically activated by hypoxia and may contribute to pulmonary vascular remodeling. This work identifies platelet activation pathways as potential circulating biomarkers and clinically relevant targets in neonatal pulmonary hypertension, expanding beyond current vasodilator-based therapies.