Abstract
During gestation, the most drastic change in oxygen supply occurs with the onset of ventilation after birth. As the too early exposure of premature infants to high arterial oxygen pressure leads to characteristic diseases, we studied the adaptation of the oxygen sensing system and its targets, the hypoxia-inducible factor- (HIF-) regulated genes (HRGs) in the developing lung. We draw a detailed picture of the oxygen sensing system by integrating information from qPCR, immunoblotting, in situ hybridization, and single-cell RNA sequencing data in ex vivo and in vivo models. HIF1α protein was completely destabilized with the onset of pulmonary ventilation, but did not coincide with expression changes in bona fide HRGs. We observed a modified composition of the HIF-PHD system from intrauterine to neonatal phases: Phd3 was significantly decreased, while Hif2a showed a strong increase and the Hif3a isoform Ipas exclusively peaked at P0. Colocalization studies point to the Hif1a-Phd1 axis as the main regulator of the HIF-PHD system in mouse lung development, complemented by the Hif3a-Phd3 axis during gestation. Hif3a isoform expression showed a stepwise adaptation during the periods of saccular and alveolar differentiation. With a strong hypoxic stimulus, lung ex vivo organ cultures displayed a functioning HIF system at every developmental stage. Approaches with systemic hypoxia or roxadustat treatment revealed only a limited in vivo response of HRGs. Understanding the interplay of the oxygen sensing system components during the transition from saccular to alveolar phases of lung development might help to counteract prematurity-associated diseases like bronchopulmonary dysplasia.
Highlights
HIF1α Protein Is Completely Destabilized with the Onset of Lung Ventilation but without Effect on the Expression of Bona Fide hypoxia-inducible factor (HIF)-regulated genes (HRGs)
This was not reflected by the expression levels of bona fide HRGs, though: Glut1, Ca9, and Trkb did not display developmental changes at all and Vegfa expression even increased from E18 onwards (Figures 1(c)–1(f))
We asked the question whether expression changes in the hypoxia-inducible factor- (HIF-)PDH system compensated for the dramatic increase of oxygen after birth to stabilize HRG expression
Summary
Transplacental oxygenation is precisely regulated by complex molecular mechanisms that control oxygen sensing and expression of downstream target genes. This system (i) requires continuous adaptation due to the logarithmic growth of the fetal body and (ii) experiences a dramatic change at birth when the low oxygen partial pressure (pO2) rapidly increases to the high levels of air-breathing life. Low oxygen tension during embryonic and fetal development is essential for proper vascular development and organogenesis. This has become evident for lung morphogenesis [1] and other organ developmental programs [2].
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