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Hypoxia-inducible Factors in the First Trimester Human Lung

Frederick Groenman, Martin Rutter, Isabella Caniggia, Dick Tibboel and Martin Post

Canadian Institutes of Health Research Group in Lung Development, Hospital for Sick Children Research Institute, Department of Pediatrics and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada (FG,MR,MP); Department of Pediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands (FG,DT); and Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada (IC)

Correspondence to: M. Post, Lung Biology Research, Physiology and Experimental Research Program, Hospital for Sick Children Research Institute, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail: martin.post{at}sickkids.ca

Lung development takes place in a relatively low-oxygen environment, which is beneficial for lung organogenesis, including vascular development. Hypoxia-inducible factor (HIF)-1 plays an important role in mediating oxygen-regulated events. HIF-1 is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel–Lindau (VHL) tumor suppressor protein leads to rapid degradation of the HIF-1 subunit. Interaction with VHL requires hydroxylation of HIF-1 proline residues by prolyl hydroxylases (PHDs). We investigated the expression of the various components regulating HIF-1 stability in first trimester (8–14 weeks) human lungs. Spatial expression was assessed by immunohistochemistry and temporal expression by quantitative PCR. Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium. PHD2 was not expressed in the airway epithelium, but in the lung parenchyma. HIF-1 and vascular endothelial growth factor (VEGF) immunoreactivity were primarily detected in the branching epithelium. HIF-2 and ARNT proteins localized to the developing epithelium as well as mesenchymal, most likely vascular, structures in the parenchyma. VEGF receptor 2 (VEGFR2) was found in the subepithelium as well as in vascular structures of the mesenchyme. All components of the VEC complex (VHL, NEDD8, and Cullin2) were found in the epithelium. Quantitative PCR analysis demonstrated that VEGF, VEGFR1, HIF-1, HIF-2, ARNT, PHD1, PHD2, PHD3, and SIAH1 gene expression was constant during early pulmonary organogenesis. Cumulatively, the data suggest that the lung develops in a low-oxygen environment that allows for proper vascular development through HIF-regulated pathways. (J Histochem Cytochem 55:355–363, 2007)

Key Words: pulmonary vascularization • hypoxia-inducible factor • development • human

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