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

Area of Science:

• Neonatal physiology
• Pulmonary vascular disease
• Cellular metabolism

Background:

• Bronchopulmonary dysplasia (BPD) in preterm infants is linked to increased mortality from pulmonary hypertension (PH).
• Current therapies for BPD-associated PH are limited, highlighting the need for novel treatment strategies.
• Endothelial carnitine palmitoyltransferase 1a (Cpt1a) plays a crucial role in cellular metabolism, but its function in neonatal PH and BPD is not well understood.

Purpose of the Study:

• To investigate the role of endothelial Cpt1a in the development of PH and pulmonary vascular remodeling in a neonatal hyperoxia model.
• To determine if Cpt1a reduction contributes to endothelial-mesenchymal transition (EndoMT) in the context of hyperoxia-induced lung injury.
• To explore potential therapeutic targets for BPD-associated PH by modulating Cpt1a levels or inhibiting EndoMT.

Main Methods:

• Utilized endothelial cell-specific Cpt1a knockout (KO) and wild-type (WT) mice exposed to hyperoxia (70% O2) from <12 hours old for 14 days, followed by recovery in normoxia.
• Assessed pulmonary hypertension (PH) and pulmonary vascular (PV) remodeling using physiological measurements and histological analyses.
• Investigated endothelial-mesenchymal transition (EndoMT) through immunofluorescence, single-cell RNA sequencing (scRNA-seq), and EC lineage tracing.

Main Results:

• Hyperoxia induced PH, which was exacerbated in EC-specific Cpt1a KO mice compared to WT controls.
• Upregulating endothelial Cpt1a expression attenuated hyperoxia-induced PV remodeling.
• Hyperoxia promoted lung EndoMT, and this process was further enhanced in EC-specific Cpt1a KO mice; blocking EndoMT ameliorated PV remodeling.
• Male mice exhibited more severe PH than females, correlating with reduced endothelial Cpt1a expression.

Conclusions:

• Neonatal hyperoxia causes PH and PV remodeling by decreasing endothelial Cpt1a expression and promoting EndoMT.
• Endothelial Cpt1a deficiency aggravates hyperoxia-induced PH and PV remodeling.
• Targeting endothelial Cpt1a upregulation or EndoMT inhibition presents a promising therapeutic strategy for BPD-associated PH.