Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Apr;32(4):851-5.
doi: 10.1161/ATVBAHA.111.226811.

Regulation of cardiovascular development by adenosine and adenosine-mediated embryo protection

Scott A Rivkees  1 , Christopher C Wendler
Affiliations
Review

Regulation of cardiovascular development by adenosine and adenosine-mediated embryo protection

Scott A Rivkees et al. Arterioscler Thromb Vasc Biol. 2012 Apr.

Abstract

Few signaling molecules have as much potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists include the methylxanthines caffeine and theophylline. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (A1AR, A2aAR, A2bAR, and A3AR). We examined how adenosine acts via A1ARs to influence embryo development. Transgenic mice were studied along with embryo cultures. Embryos lacking A1ARs were markedly growth retarded following intrauterine hypoxia exposure. Studies of mice selectively lacking A1AR in the heart identify the heart as a key site of adenosine's embryo-protective effects. Studies of isolated embryos showed that adenosine plays a key role in modulating embryo cardiac function, especially in the setting of hypoxia. When pregnant mice were treated during embryogenesis with the adenosine antagonist caffeine, adult mice had abnormal heart function. Adenosine acts via A1ARs to play an essential role in protecting the embryo against intrauterine stress, and adenosine antagonists, including caffeine, may be an unwelcome exposure for the embryo.

PubMed Disclaimer

Conflict of interest statement

Disclosures: There are no conflicts to report.

Figures

Figure 1
Figure 1. A1ARs protects against growth retardation in embryos
Hypoxia induces severe growth retardation in A1AR−/− embryos. Dams were exposed to 10% O2 from E8.5 to E12.5. C–R length was measured for normoxia and hypoxia-treated embryos at E12.5. Under normoxia conditions (A). A1AR+/− embryos were indistinguishable from A1AR−/− (B) embryos. Under hypoxic conditions, A1AR+/− embryos (C) were smaller then the normoxic controls (A), but A1AR−/− embryos (D) were significantly smaller than A1AR−/− or A1AR+/− normoxic embryos. A1AR−/− hypoxic hearts (H) were smaller than A1AR+/− normoxic (E), A1AR−/− normoxic (F), or A1AR+/− hypoxic hearts (G). Scale bars: 1 mm.
Figure 2
Figure 2. Cartoon depicting contribution of adenosine to protecting the embryo against intrauterine stress and how this is disrupted by caffeine
See this image and copyright information in PMC

References

    1. Jacobson KA. Introduction to adenosine receptors as therapeutic targets. Handb Exp Pharmacol. 2009:1–24. - PMC - PubMed
    1. Rivkees SA, Zhao Z, Porter G, Turner C. Influences of adenosine on the fetus and newborn. Mol Genet Metab. 2001;74:160–171. - PubMed
    1. Eckle T, Koeppen M, Eltzschig HK. Role of extracellular adenosine in acute lung injury. Physiology (Bethesda) 2009;24:298–306. - PubMed
    1. Eltzschig HK, Weissmuller T, Mager A, Eckle T. Nucleotide metabolism and cell-cell interactions. Methods Mol Biol. 2006;341:73–87. - PubMed
    1. Conway SJ, Kruzynska-Frejtag A, Kneer PL, Machnicki M, Koushik SV. What cardiovascular defect does my prenatal mouse mutant have, and why? Genesis. 2003;35:1–21. - PubMed

Publication types

MeSH terms