© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1
aCenter for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
bDepartment of Experimental Biology, University of Jaen, 23071 Jaen, Spain
cDepartment of Anatomy and Embryology, Academic Medical Center University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
*Corresponding author. Tel.: +32-16-34-57-72; fax: +32-16-34-59-90. Email address: peter.carmeliet{at}med.kuleuven.ac.be
Objectives: Previous studies have revealed the essential role of hypoxia-inducible factor-1
(HIF-1), 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-1 (HIF-1–/–). Methods: We analyzed cardiovascular development in HIF-1–/– 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-1 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-1–/– 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-1–/– embryos. Conclusion: HIF-1 is essential for proper cardiac development by modulating both neural crest migration and ventricle formation.
KEYWORDS Developmental biology; Embryology; Morphogenesis; Myocytes; Endothelins
1 Tel.: +34-953-002763; fax: +34-953-012141.
2 Tel.: +31-20-566-49-28; fax: +31-20-697-61-77.
* Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cardiores.2003.07.003.
Time for primary review 37 days
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