Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1alpha.
OBJECTIVE
Previous studies have revealed the essential role of hypoxia-inducible factor-1alpha (HIF-1alpha), a basic helix-loop-helix transcription factor, in cardiovascular development. We attempted to further characterize the underlying mechanisms resulting in abnormal cardiogenesis and defective angiogenesis in mice deficient for HIF-1alpha (HIF-1alpha(-/-)).


METHODS
We analyzed cardiovascular development in HIF-1alpha(-/-) embryos at both the macroscopic and microscopic level. Gene expression was determined by RT-PCR, in situ hybridization and immunohistochemistry. Embryonic survival was studied using whole embryo culture.


RESULTS
HIF-1alpha deficiency caused cardia bifida in some embryos, while cardiac looping was disturbed in others. These defects did not result from abnormal cardiomyocyte commitment or differentiation, but may relate to defective ventricle formation caused by reduced expression of myocyte enhancer factor 2C (MEF2C) and eHAND. In addition, remodeling of the aortic outflow tract and cephalic blood vessels was abnormal in HIF-1alpha(-/-) embryos. These malformations, together with the hypoplastic pharyngeal arches, are presumably induced by defective neural crest cell (NCC) migration. Impaired migration might be related to insufficient levels of semaphorin-3A (Sema3A). Hyperoxia prolonged survival but only partially rescued the developmental program of cultured HIF-1alpha(-/-) embryos.


CONCLUSIONS
HIF-1alpha is essential for proper cardiac development by modulating both neural crest migration and ventricle formation.
Compernolle
Veerle
V
Flanders Interuniversitary Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Brusselmans
Koen
K
Franco
Diego
D
Moorman
Antoon
A
Dewerchin
Mieke
M
Collen
Désiré
D
Carmeliet
Peter
P
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics*; D000818:Animals; D002319:Cardiovascular System / Q000196:embryology*; D046508:Culture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics*; D005313:Fetal Death; D015870:Gene Expression; D006330:Heart Defects, Congenital / Q000196:embryology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D018919:Neovascularization, Physiologic; D009432:Neural Crest / Q000002:abnormalities; D009687:Nuclear Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors