{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:54:28Z","timestamp":1791093268232,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2008,1,9]],"date-time":"2008-01-09T00:00:00Z","timestamp":1199836800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>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 A<jats:sub>1<\/jats:sub> adenosine receptors (A<jats:sub>1<\/jats:sub>ARs).<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>To examine the influences of hypoxia and adenosine signaling on cardiac development, chicken embryos were studied. Real time RT\u2010PCR assay was used to examine the <jats:italic>A<\/jats:italic><jats:sub><jats:italic>1<\/jats:italic><\/jats:sub><jats:italic>AR<\/jats:italic> gene expression during embryogenesis and after siRNA\u2010 mediated knock down. Cell proliferation was determined by counting cell nuclei and PhosphoHistone H3 positive cells. Apoptosis was determined by TUNEL assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>A<jats:sub>1<\/jats:sub>ARs were found to be expressed in chicken embryos during early embryogenesis. Treatment of Hamburger and Hamilton stage 4 embryos with the A<jats:sub>1<\/jats:sub>AR agonist N<jats:sup>6<\/jats:sup>\u2010cyclopentyladenosine 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\u2010induced abnormalities were reduced when A<jats:sub>1<\/jats:sub>AR signaling was inhibited by the A<jats:sub>1<\/jats:sub>AR antagonist 1,3 dipropyl\u20108\u2010cyclopentylxanthine or by siRNA\u2010targeting A<jats:sub>1<\/jats:sub>ARs. Hypoxia treatment did not increase apoptosis, but decreased embryonic cell proliferation.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>These data indicate that hypoxia adversely influences cardiac malformations during development, in part by A<jats:sub>1<\/jats:sub>AR signaling. 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