Nature Medicine
8, 702 - 710 (2002)
Published online: 10 June 2002; | doi:10.1038/nm721
There is a Corrigendum (November 2002) associated with this Article.
Loss of HIF-2 and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature miceVeerle Compernolle1, Koen Brusselmans1, Till Acker2, Peter Hoet3, Marc Tjwa1, Heike Beck2, Stéphane Plaisance1, Yuval Dor4, Eli Keshet4, Florea Lupu5, Benoit Nemery3, Mieke Dewerchin1, Paul Van Veldhoven6, Karl Plate2, Lieve Moons1, Désiré Collen1
& Peter Carmeliet11
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
2
Neurological Institute, JWG Frankfurt University, Frankfurt, Germany
3
Laboratory of Pneumology, Unit of Lung Toxicology, KU Leuven, Leuven, Belgium
4
Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel
5
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
6
Department of Pharmacology, KU Leuven, Leuven, Belgium
Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beRespiratory distress syndrome (RDS) due to insufficient production of surfactant is a common and severe complication of preterm delivery. Here, we report that loss of the hypoxia-inducible transcription factor-2 (HIF-2) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2-deficient fetuses; mice with a deficiency of the VEGF164 and VEGF188 isoforms or of the HIF-binding site in the VEGF promotor died of RDS; intrauterine delivery of anti-VEGF-receptor-2 antibodies caused RDS and VEGF stimulated production of surfactant proteins by cultured type 2 pneumocytes. Intrauterine delivery or postnatal intratracheal instillation of VEGF stimulated conversion of glycogen to surfactant and protected preterm mice against RDS. The pneumotrophic effect of VEGF may have therapeutic potential for lung maturation in preterm infants.
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