A1 adenosine receptors play an essential role in protecting the embryo against hypoxia

Embryos can be exposed to environmental factors that induce hypoxia. Currently, our understanding of the effects of hypoxia on early mammalian development is modest. Potential mediators of hypoxia action include the nucleoside adenosine, which acts through A(1) adenosine receptors (A(1)ARs) and mediates adverse effects of hypoxia on the neonatal brain. We hypothesized that A(1)ARs may also play a role in mediating effects of hypoxia on the embryo. When pregnant dams were exposed to hypoxia (10% O(2)) beginning at embryonic day (E) 7.5 or 8.5 and continued for 24-96 h, A(1)AR+/+ embryos manifested growth inhibition and a disproportionate reduction in heart size, including thinner ventricular walls. Yet, when dams were exposed to hypoxia, embryos lacking A(1)ARs (A(1)AR-/-) had much more severe growth retardation than A(1)AR+/+ or +/- embryos. When levels of hypoxia-inducible factor 1alpha (HIF1alpha) were examined, A(1)AR-/- embryos had less stabilized HIF1alpha protein than A(1)AR+/- littermates. Normal patterns of cardiac gene expression were also disturbed in A(1)AR-/- embryos exposed to hypoxia. These results show that short periods of hypoxia during early embryogenesis can result in intrauterine growth retardation. We identify adenosine and A(1)ARs as playing an essential role in protecting the embryo from hypoxia.