Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies.

Jamie Wikenheiser, Julie A. Wolfram, Madhusudhana Gargesha, K. Yang, Ganga Karunamuni, David L. Wilson, Gregg L. Semenza, Faton Agani, Steven A. Fisher, Nicole Ward, Michiko Watanabe

Research output: Contribution to journalArticlepeer-review


The outflow tract myocardium and other regions corresponding to the location of the major coronary vessels of the developing chicken heart, display a high level of hypoxia as assessed by the hypoxia indicator EF5. The EF5-positive tissues were also specifically positive for nuclear-localized hypoxia inducible factor-1 alpha (HIF-1alpha), the oxygen-sensitive component of the hypoxia inducible factor-1 (HIF-1) heterodimer. This led to our hypothesis that there is a "template" of hypoxic tissue that determines the stereotyped pattern of the major coronary vessels. In this study, we disturbed this template by altering ambient oxygen levels (hypoxia 15%; hyperoxia 75-40%) during the early phases of avian coronary vessel development, in order to alter tissue hypoxia, HIF-1alpha protein expression, and its downstream target genes without high mortality. We also altered HIF-1alpha gene expression in the embryonic outflow tract cardiomyocytes by injecting an adenovirus containing a constitutively active form of HIF-1alpha (AdCA5). We assayed for coronary anomalies using anti-alpha-smooth muscle actin immunohistology. When incubated under abnormal oxygen levels or injected with a low titer of the AdCA5, coronary arteries displayed deviations from their normal proximal connections to the aorta. These deviations were similar to known clinical anomalies of coronary arteries. These findings indicated that developing coronary vessels may be subject to a level of regulation that is dependent on differential oxygen levels within cardiac tissues and subsequent HIF-1 regulation of gene expression.

Original languageEnglish (US)
Pages (from-to)2688-2700
Number of pages13
JournalDevelopmental dynamics : an official publication of the American Association of Anatomists
Issue number10
StatePublished - Oct 2009
Externally publishedYes

ASJC Scopus subject areas

  • Developmental Biology


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