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Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice

Nature Medicine volume 8, pages 702–710 (2002)Cite this article

A Corrigendum to this article was published on 01 November 2002

Abstract

Respiratory 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-2α (HIF-2α) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2α, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2α-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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Figure 1: Impaired lung maturation and RDS in HIF-2α−/− mice.
Figure 2: Pulmonary vascular development in HIF-2α−/− mice.
Figure 3: Pulmonary expression of HIF-2α, VEGF and its receptors.
Figure 4: VEGF treatment improves lung maturation and protects against respiratory distress.

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Acknowledgements

We thank R. Verbesselt, K. Desmet, C. Van Geet and H. Devlieger for helpful discussion; and A. Bouché, M. De Mol, B. Hermans, S. Jansen, L. Kieckens, W.Y. Man, A. Manderveld, K. Maris, W. Martens, M. Nijs, S. Terclavers, A. Vandenhoeck, B. Vanwetswinkel, P. Van Wezemael and S. Wyns for technical assistance. This work was supported by an FWO-fellowship to V.C. and S.P. and by grants from the Research Fund K.U.Leuven (GOA/2001/09) and the BIOMED (#PL963380) to P.C. and D.C.

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Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

    Veerle Compernolle, Koen Brusselmans, Marc Tjwa, Stéphane Plaisance, Mieke Dewerchin, Lieve Moons, Désiré Collen & Peter Carmeliet

  2. Neurological Institute, JWG Frankfurt University, Frankfurt, Germany

    Till Acker, Heike Beck & Karl Plate

  3. Laboratory of Pneumology, Unit of Lung Toxicology, KU Leuven, Leuven, Belgium

    Peter Hoet & Benoit Nemery

  4. Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

    Yuval Dor & Eli Keshet

  5. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

    Florea Lupu

  6. Department of Pharmacology, KU Leuven, Leuven, Belgium

    Paul Van Veldhoven

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Correspondence to Peter Carmeliet.

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Compernolle, V., Brusselmans, K., Acker, T. et al. Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8, 702–710 (2002). https://doi.org/10.1038/nm721

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