Oxygen-sensing pathways and the development of mammalian gas exchange

Oxygen-sensing pathways have been extensively explored in the context of homeostatic responses to hypoxic episodes; however, little is known of their involvement in the morphogenesis of respiratory structures (mitochondria, placenta, lung) during development in utero. This review identifies four essential loci where oxygen signalling pathways may cue the development of respiratory structures as: (i). mitochondrial biogenesis coupled with muted oxidative function dependent on the hypoxia-sustained production of NO; (ii). the generation of oxygen gradients which drive trophoblast differentiation and the formation of the chorionic gas exchange interface of the placenta; (iii). the proliferation and epithelial/endothelial differentiation of mesenchyme during the initiation of lung morphogenesis; and (iv). the regulation of epithelial fluid secretion/absorption in the lung. The identification of these oxygen-regulated developmental stages clarifies the close association between oxygen availability, reactive oxygen species and the morphogenesis of gas exchange structures and bears with it the implication that these pathways set the scope for aerobic metabolic performance throughout life.