Role of A1 adenosine receptors in mitigating the effects of hypoxia on embryonic and cardiac development

Abstract

Hypoxia exposure during embryonic development is associated with intra-uterine growth retardation and is induced by placental insufficiency, maternal smoking, and other factors. One possible mediator of intra-uterine hypoxia effects is the nucleoside adenosine whose levels rise markedly in hypoxia. Adenosine binds A1 adenosine receptors (A1ARs) which are expressed in cardiac and nervous tissue. An in utero model of hypoxia was used to examine acute and long term effects of embryonic hypoxia exposure. When pregnant dams were placed in a chamber to maintain 10% O2 for 6 to 96 hours, developing embryos displayed widespread tissue hypoxia (less than 10 mm of Hg). Hypoxic exposure of wild type embryos as well as A1AR knockout embryos (A1AR+/− and A1AR−/−) resulted in embryonic growth inhibition and a reduction in heart size. A1AR −/− embryos were the most adversely affected including greater growth inhibition, more embryos with severe growth retardation (50% reduction in size), greater percent of reabsorbed embryos, and thinner ventricular walls. One target of A1AR signaling may be hypoxia-inducible factor 1a (HIF1a) since A1AR−/− embryos have much less HIF1a protein after hypoxia compared to A1AR +/− littermates. These results indicate that A1AR activity contributes to the protection of the embryo during hypoxic insults and may mediate this effect through stabilization of HIF1a protein. Supported by NIH (HL58442).