Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1{alpha}

doi:10.1016/j.cardiores.2003.07.003

Cardiovascular Research 2003 60(3):569-579; doi:10.1016/j.cardiores.2003.07.003
© 2003 by European Society of Cardiology

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Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1 ${alpha}$

Veerle Compernolle^a, Koen Brusselmans^a, Diego Franco^b^,1, Antoon Moorman^c^,2, Mieke Dewerchin^a, Désiré Collen^a and Peter Carmeliet^*^,a

^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 roleof hypoxia-inducible factor-1 ${alpha}$ (HIF-1 ${alpha}$ ), a basic helix-loop-helixtranscription factor, in cardiovascular development. We attemptedto further characterize the underlying mechanisms resultingin abnormal cardiogenesis and defective angiogenesis in micedeficient for HIF-1 ${alpha}$ (HIF-1 ${alpha}$ ^–/–). Methods: We analyzedcardiovascular development in HIF-1 ${alpha}$ ^–/– embryos atboth the macroscopic and microscopic level. Gene expressionwas determined by RT-PCR, in situ hybridization and immunohistochemistry.Embryonic survival was studied using whole embryo culture. Results:HIF-1 ${alpha}$ deficiency caused cardia bifida in some embryos, whilecardiac looping was disturbed in others. These defects did notresult from abnormal cardiomyocyte commitment or differentiation,but may relate to defective ventricle formation caused by reducedexpression of myocyte enhancer factor 2C (MEF2C) and eHAND.In addition, remodeling of the aortic outflow tract and cephalicblood vessels was abnormal in HIF-1 ${alpha}$ ^–/– embryos.These malformations, together with the hypoplastic pharyngealarches, are presumably induced by defective neural crest cell(NCC) migration. Impaired migration might be related to insufficientlevels of semaphorin-3A (Sema3A). Hyperoxia prolonged survivalbut only partially rescued the developmental program of culturedHIF-1 ${alpha}$ ^–/– embryos. Conclusion: HIF-1 ${alpha}$ is essentialfor proper cardiac development by modulating both neural crestmigration 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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