Background: Fetal lung development requires proper coordination between lung epithelial and vascular morphogenesis. A major determinant in lung vascular development is vascular endothelial growth factor (VEGF), which is regulated by hypoxia-inducible factors (HIFs). VEGF is expressed in the airway epithelium, while its receptors (VEGFRs) are expressed in the pulmonary mesenchyme. The hypoxic environment in utero is beneficial for fetal organogenesis, especially vascular development. However, little is known about the expression of HIFs and VEGFR-2 in the human fetal lung in vitro. Objectives: The purpose of this study was to investigate the effects of hypoxia on fetal lung morphology and mRNA expression of VEGF, VEGFR-2, HIF-2α, and HIF-3α. Methods: An explant culture technique was used to study the effects of normoxic and hypoxic conditions on human fetal lung. Results: The morphology remained largely unchanged in explants cultured under hypoxic or normoxic conditions. Quantitative RT-PCR showed that the mRNA expression of VEGF-A, but not VEGFR-2 is upregulated in explants cultured at 1.5% compared with 21% oxygen. We observed a nonsignificant increase in HIF-2α and HIF-3α mRNA expression in explants cultured at 1.5% oxygen. These data suggest that the mRNA expression of VEGF, and possibly HIF-2α and HIF-3α, is regulated by hypoxia in the developing human lung. Conclusion: This lung explant culture model appears to be a valuable model to unravel the molecular mechanisms of human lung development.

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Keywords CD31 antigen, Fetal lung development, Hypoxia-inducible factors, Ki 67 antigen, Morphogenesis, Vascular endothelial growth factor, article, biological marker, cell differentiation, controlled study, explant, fetus lung, gene expression regulation, human, human tissue, hypoxia, hypoxia inducible factor, hypoxia inducible factor 2alpha, hypoxia inducible factor 3alpha, immunohistochemistry, lung development, messenger RNA, morphology, oxygen, priority journal, protein expression, protein function, quantitative analysis, real time polymerase chain reaction, reverse transcription polymerase chain reaction, thyroid transcription factor 1, unclassified drug, vasculotropin, vasculotropin A, vasculotropin receptor 2
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Journal Neonatology: fetal and neonatal research
Rajatapiti, P, de Rooij, J.D, Beurkens, L.W.J.E, Keijzer, R, Tibboel, D, Rottier, R.J, & de Krijger, R.R. (2010). Effect of oxygen on the expression of hypoxia-inducible factors in human fetal lung explants. Neonatology: fetal and neonatal research, 97(4), 346–354. doi:10.1159/000261018