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

Nat Med. 2002 Jul;8(7):702-10. doi: 10.1038/nm721. Epub 2002 Jun 10.

Authors

Veerle Compernolle¹, 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

Affiliation

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

PMID: 12053176
DOI: 10.1038/nm721

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-2alpha (HIF-2alpha) caused fatal RDS in neonatal mice due to insufficient surfactant production by alveolar type 2 cells. VEGF, a target of HIF-2alpha, regulates fetal lung maturation: because VEGF levels in alveolar cells were reduced in HIF-2alpha-deficient fetuses; mice with a deficiency of the VEGF(164) and VEGF(188) 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aging
Animals
Basic Helix-Loop-Helix Transcription Factors
Disease Models, Animal
Endothelial Growth Factors / pharmacology
Endothelial Growth Factors / physiology*
Lung / drug effects
Lung / growth & development
Lung / pathology
Lung / physiopathology
Lung Diseases / pathology
Lung Diseases / physiopathology
Lung Diseases / prevention & control*
Lymphokines / pharmacology
Lymphokines / physiology*
Mice
Mice, Knockout
Mice, Transgenic
Pulmonary Alveoli / growth & development
Pulmonary Alveoli / pathology
Respiratory Distress Syndrome / pathology
Respiratory Mucosa / pathology
Respiratory Mucosa / physiopathology
Trans-Activators / deficiency
Trans-Activators / genetics
Trans-Activators / physiology*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Substances

Basic Helix-Loop-Helix Transcription Factors
Endothelial Growth Factors
Lymphokines
Trans-Activators
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
endothelial PAS domain-containing protein 1