Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice.
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.
Compernolle
Veerle
V
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity, Institute for Biotechnology, Leuven, Belgium.
Brusselmans
Koen
K
Acker
Till
T
Hoet
Peter
P
Tjwa
Marc
M
Beck
Heike
H
Plaisance
Stéphane
S
Dor
Yuval
Y
Keshet
Eli
E
Lupu
Florea
F
Nemery
Benoit
B
Dewerchin
Mieke
M
Van Veldhoven
Paul
P
Plate
Karl
K
Moons
Lieve
L
Collen
Désiré
D
Carmeliet
Peter
P
D000375:Aging; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000494:pharmacology / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000254:growth & development / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology / Q000503:physiopathology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1