Expression of hypoxia-inducible factors in normal human lung development

P (Prapapan) Rajatapiti, IWJM Horst, Judith de Rooij, MGB Tran, PH Maxwell, Dick Tibboel, Robbert Rottier, Ronald de Krijger

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Abstract

Pulmonary vascular development is essential for proper lung development, and its disturbance can lead to neonatal morbidity and mortality, as exemplified in congenital diaphragmatic hernia. Hypoxia-inducible factors (HIFs) appear to be key molecules in physiologic angiogenesis and in certain forms of lung pathology, such as bronchopulmonary dysplasia. Little is known about the qualitative and quantitative expression of HIFs in normal human fetal lung development. Therefore, we investigated the expression of HIT-1 alpha, HIF-2 alpha, and HIF-3 alpha, along with their upstream regulators and downstream targets, von Hippel-Lindau protein, vascular endothelial growth factor A (VEGF-A), and its receptor, VEGFR-2, in 20 normal human fetal lungs (13.5 weeks in gestation until term) and 5 adult lungs. Quantitative polymerase chain reaction demonstrated a positive correlation between HIF-2 alpha and VEGF-A expression and gestational age. Although there appeared to be a decreasing trend in HIF-3 alpha expression during pregnancy, it did not reach statistical significance. Immunohistochemistry for HIF-1 alpha and HIF-2 alpha revealed that HIF-1 alpha is expressed in the epithelium, while HIF-2 alpha is expressed in both interstitium and epithelium. Our data indicate that HlFs, most notably HIF-2 alpha, appear to exert an important role in angiogenesis during human fetal lung development, especially in the last phases of pregnancy, preparing the fetus for extrauterine life. As such, our results form the baseline data for the evaluation and interpretation of abnormal pulmonary vascular development.
Original languageUndefined/Unknown
Pages (from-to)193-199
Number of pages7
JournalPediatric and Developmental Pathology
Volume11
Issue number3
DOIs
Publication statusPublished - 2008

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