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

Veerle Compernolle; Koen Brusselmans; Till Acker; Peter Hoet; Marc Tjwa; Heike Beck; Stéphane Plaisance; Yuval Dor; Eli Keshet; Florea Lupu; Benoit Nemery; Mieke Dewerchin; Paul Van Veldhoven; Karl Plate; Lieve Moons; Désiré Collen; Peter Carmeliet

doi:10.1038/nm721

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

Veerle Compernolle, Koen Brusselmans, Till Acker, Peter Hoet, Marc Tjwa, Heike Beck, Stéphane Plaisance, Yuval Dor, Eli Keshet, Florea Lupu, Benoit Nemery, Mieke Dewerchin, Paul Van Veldhoven, Karl Plate, Lieve Moons, Désiré Collen, Peter Carmeliet

Department of Developmental Biology and Cancer Research

Research output: Contribution to journal › Article › peer-review

651 Scopus citations

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.

Original language	English
Pages (from-to)	702-710
Number of pages	9
Journal	Nature Medicine
Volume	8
Issue number	7
DOIs	https://doi.org/10.1038/nm721
State	Published - Jul 2002

Bibliographical note

Funding Information:
Acknowledgments 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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Compernolle, V., Brusselmans, K., Acker, T., Hoet, P., Tjwa, M., Beck, H., Plaisance, S., Dor, Y., Keshet, E., Lupu, F., Nemery, B., Dewerchin, M., Van Veldhoven, P., Plate, K., Moons, L., Collen, D., & Carmeliet, P. (2002). 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, 8(7), 702-710. https://doi.org/10.1038/nm721

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

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.",

author = "Veerle Compernolle and Koen Brusselmans and Till Acker and Peter Hoet and Marc Tjwa and Heike Beck and St{\'e}phane Plaisance and Yuval Dor and Eli Keshet and Florea Lupu and Benoit Nemery and Mieke Dewerchin and {Van Veldhoven}, Paul and Karl Plate and Lieve Moons and D{\'e}sir{\'e} Collen and Peter Carmeliet",

note = "Funding Information: Acknowledgments We thank R. Verbesselt, K. Desmet, C. Van Geet and H. Devlieger for helpful discussion; and A. Bouch{\'e}, 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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Compernolle, V, Brusselmans, K, Acker, T, Hoet, P, Tjwa, M, Beck, H, Plaisance, S, Dor, Y, Keshet, E, Lupu, F, Nemery, B, Dewerchin, M, Van Veldhoven, P, Plate, K, Moons, L, Collen, D & Carmeliet, P 2002, '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, vol. 8, no. 7, pp. 702-710. https://doi.org/10.1038/nm721

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T1 - Loss of HIF-2α and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice

AU - Compernolle, Veerle

AU - Brusselmans, Koen

AU - Acker, Till

AU - Hoet, Peter

AU - Tjwa, Marc

AU - Beck, Heike

AU - Plaisance, Stéphane

AU - Dor, Yuval

AU - Keshet, Eli

AU - Lupu, Florea

AU - Nemery, Benoit

AU - Dewerchin, Mieke

AU - Van Veldhoven, Paul

AU - Plate, Karl

AU - Moons, Lieve

AU - Collen, Désiré

AU - Carmeliet, Peter

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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

Abstract

Bibliographical note

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