Endothelial Cpt1a Inhibits Neonatal Hyperoxia-Induced Pulmonary Vascular Remodeling by Repressing Endothelial-Mesenchymal Transition

Xiaoyun Li, Katy Hegarty, Fanjie Lin, Jason L. Chang, Amro Abdalla, Karthik Dhanabalan, Sergey O. Solomevich, Wenliang Song, Karim Roder, Chenrui Yao, Wenju Lu, Peter Carmeliet, Gaurav Choudhary, Phyllis A. Dennery, and Hongwei Yao
Brown University. Providence VA Medical Center. Warren Alpert Medical School of Brown University. Jinan University. First Affiliated Hospital of Guangzhou Medical University. Boston University. KU Leuven. Khalifa University.
United States, China, Belgium and United Arab Emirates

Advanced Science
Adv Sci 2025;
DOI: 10.1002/advs.202415824

Abstract
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.

Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Pulmonary Vascular Pathology

Age Focus: Pediatric Pulmonary Vascular Disease

Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication

Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes

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