Pulmonary hypertension (PH) increases the mortality of preterm infants with bronchopulmonary dysplasia (BPD). There are no curative therapies for this disease. Lung endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme of the carnitine shuttle system, is reduced in a rodent model of BPD. It is unknown whether endothelial Cpt1a reduction causes pulmonary vascular (PV) remodeling. The latter can be the result of endothelial-mesenchymal transition (EndoMT). Here, endothelial cell (EC)-specific Cpt1a KO and WT mice (<12 h old) are exposed to hyperoxia (70% O2) for 14 days and allow them to recover in normoxia until postnatal day 28. Hyperoxia causes PH, which is aggravated in EC-specific Cpt1a KO mice. Upregulating endothelial Cpt1a expression inhibits hyperoxia-induced PV remodeling. Hyperoxia causes lung EndoMT, detected by immunofluorescence, scRNA-sequencing, and EC lineage tracing, which is further increased in EC-specific Cpt1a KO mice. Blocking EndoMT inhibits hyperoxia-induced PV remodeling. Male mice under the same high oxygen conditions develop a higher degree of PH than females, which is associated with reduced endothelial Cpt1a expression. Conclusively, neonatal hyperoxia causes PH by decreasing endothelial Cpt1a expression and upregulating EndoMT. This provides a valuable strategy for developing targeted therapies by upregulating endothelial Cpt1a levels or inhibiting EndoMT to treat BPD-associated PH.
Keywords: bronchopulmonary dysplasia; metabolic reprograming; nanoparticle‐mediated gene delivery; pulmonary hypertension; single‐cell RNA transcriptomics.
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.