Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease

Abstract

Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O 2 ). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Ra gene in preterms with nCLD and directly test the effect of PDGF-Ra haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O 2 . In the context of MV-O 2 , attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Ra-dependent reduction in lung VEGF-A. TGF-b contributes to the PDGF-Ra-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O 2 . Overall, our results establish attenuated PDGF signaling as an important driver of nCLD pathology with provision of PDGF-A as a protective strategy for newborns undergoing MV-O 2 .