Metabolic mechanisms underlying bronchopulmonary dysplasia-associated pulmonary hypertension

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SUMMARY Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, caused by mechanical ventilation and hyperoxia amongst other factors. Thirty percent of infants with BPD develop pulmonary hypertension (PH), characterized by pulmonary vascular (PV) remodeling. There are no curative therapies for this disease. My long-term goal is to develop novel targeted therapies to treat BPD associated PH (BPD-PH). PV remodeling is characterized by increased pulmonary arterial media layer thickening. This results from proliferation of vascular smooth muscle cells (SMCs), or transdifferentiation from endothelial cells (ECs) to SMCs (i.e., endothelial-mesenchymal transition, EndoMT). We have shown that hyperoxia in newborn mice and mechanical ventilation in preterm lambs cause PV remodeling resulting in PH, which is associated with increased EndoMT. We preliminarily show that EndoMT is also observed in the lung of premature human infants requiring mechanical ventilation. Blocking EndoMT prevents the progression of neonatal hyperoxia-induced PV remodeling and PH in mice, suggesting that EndoMT plays a causative role in inducing PH. We observed no increase in EdU incorporation into SMCs in hyperoxia-exposed mice, suggesting proliferation in these cells does not contribute to PV remodeling in BPD-PH. We recently reported that neonatal hyperoxia causes a persistent reduction of endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme of the carnitine shuttle system responsible for transporting long-chain fatty acids into mitochondria for β-oxidation during fatty acid oxidation. Our preliminary data show that lung Cpt1a gene expression is also reduced in mechanically ventilated preterm lambs and premature human infants. Additionally, endothelial deletion of Cpt1a increases EndoMT and PV remodeling in neonatal mice after exposure to hyperoxia. Furthermore, pharmacological upregulation of Cpt1a attenuates EndoMT in vitro and prevents PV remodeling in neonatal mice in response to hyperoxia. Whether neonatal hyperoxia and mechanical ventilation reduce endothelial Cpt1a, leading to PH is yet to be determined. The central hypothesis is that neonatal hyperoxia and mechanical ventilation cause EndoMT by downregulating endothelial Cpt1a levels, thereby resulting in PV remodeling and PH. We will test this hypothesis in three Specific Aims. Aim 1 will determine the molecular mechanisms by which Cpt1a downregulation contributes to EndoMT. In Aim 2, we will define the contribution of endothelial Cpt1a reduction to BPD-PH and EndoMT. In Aim 3, we will evaluate endothelial Cpt1a as a therapeutic target for BPD-PH using both lamb and mouse models. The combination of clinically relevant lamb and mouse models with our newly generated EC-specific Cpt1a KO mice and the novel EC-targeted nanoparticle delivery system provides an innovative approach to uncover the mechanisms by which Cpt1a downregulation mediates EndoMT and its significant roles in BPD-PH. This contribution is significant because it is likely to result in new therapies specifically targeting endothelial Cpt1a or EndoMT in neonates to treat BPD-PH.