Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease
Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen-rich gas (MV-O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF-Rα gene in preterms with nCLD and directly test the effect of PDGF-Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV-O2. In the context of MV-O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF-Rα-dependent reduction in lung VEGF-A. TGF-β contributes to the PDGF-Rα-dependent decrease in myofibroblast function. Remarkably, endotracheal treatment with exogenous PDGF-A rescues both the lung defects in haploinsufficient mice undergoing MV-O2. 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-O2.
|Keywords||bronchopulmonary dysplasia, neonatal chronic lung disease, PDGF-Rα, transforming growth factor-β, VEGF-A|
|Persistent URL||dx.doi.org/10.15252/emmm.201607308, hdl.handle.net/1765/102723|
|Journal||EMBO Molecular Medicine|
Oak, P. (Prajakta), Pritzke, T. (Tina), Thiel, I. (Isabella), Koschlig, M. (Markus), Mous, D.S, Windhorst, A. (Anita), … Hilgendorff, A. (2017). Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease. EMBO Molecular Medicine, 9(11), 1504–1520. doi:10.15252/emmm.201607308