Hypoxia induces cardiac malformations via A1 adenosine receptor activation in chicken embryos

Satish K. Ghatpande, Charles J. Billington, Scott A. Rivkees, Christopher C. Wendler

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


BACKGROUND: The current understanding of the effects of hypoxia on early embryogenesis is limited. Potential mediators of hypoxic effects include adenosine, which increases dramatically during hypoxic conditions and activates A1 adenosine receptors (A1ARs). METHODS: To examine the influences of hypoxia and adenosine signaling on cardiac development, chicken embryos were studied. Real time RT-PCR assay was used to examine the A 1AR gene expression during embryogenesis and after siRNA- mediated knock down. Cell proliferation was determined by counting cell nuclei and PhosphoHistone H3 positive cells. Apoptosis was determined by TUNEL assay. RESULTS: A1ARs were found to be expressed in chicken embryos during early embryogenesis. Treatment of Hamburger and Hamilton stage 4 embryos with the A1AR agonist N6-cyclopentyladenosine caused cardiac bifida and looping defects in 55% of embryos. Hamburger and Hamilton stage 4 embryos exposed to 10% oxygen for 6, 12, 18, and 24 h followed by recovery in room air until stage 11, exhibited cardia bifida and looping defects in 34, 45, 60, and 86% of embryos respectively. Hypoxia-induced abnormalities were reduced when A1AR signaling was inhibited by the A1AR antagonist 1,3 dipropyl-8-cyclopentylxanthine or by siRNA-targeting A1ARs. Hypoxia treatment did not increase apoptosis, but decreased embryonic cell proliferation. CONCLUSIONS: These data indicate that hypoxia adversely influences cardiac malformations during development, in part by A1AR signaling.

Original languageEnglish (US)
Pages (from-to)121-130
Number of pages10
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Issue number3
StatePublished - Mar 2008


  • Adenosine
  • Adenosine receptor
  • Chicken embryo
  • Heart
  • Hypoxia


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