Local tissue oxygenation profoundly influences placental development. To elucidate the impact of
hypoxia on cellular and molecular adaptation in vivo, pregnant mice at embryonic days 7.5-11.5 were exposed to reduced environmental
oxygen (6-7% O2) for various periods of time.
Hypoxia-inducible factor (HIF)-1alpha
mRNA was highly expressed in the placenta, whereas HIF-2alpha was predominantly found in the decidua, indicating that HIF-1 is a relevant
oxygen-dependent factor involved in placental development. During severe
hypoxia, HIF-1alpha
protein was strongly induced in the periphery but, however, not in the labyrinth layer of the placenta. Accordingly, no indication for tissue
hypoxia in this central area was detected with
2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide staining and
VEGF expression as hypoxic markers. The absence of significant tissue
hypoxia was reflected by preserved placental architecture and trophoblast differentiation. In the search for mechanisms preventing local
hypoxia, we found upregulation of
endothelial nitric oxide synthase (NOS) expression in the labyrinth layer. Inhibition of NOS activity by
N(omega)-nitro-L-arginine methyl ester application resulted in ubiquitous placental tissue
hypoxia. Our results show that placental oxygenation is preserved even during severe systemic
hypoxia and imply that NOS-mediated mechanisms are involved to protect the placenta from maternal
hypoxia.