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Placental α2-adrenoceptors control vascular development at the interface between mother and embryo

Nature Genetics volume 31, pages 311–315 (2002)Cite this article

Abstract

A substantial percentage of human pregnancies are lost as spontaneous abortions after implantation. This is often caused by an inadequately developed placenta. Proper development of the placental vascular system is essential to nutrient and gas exchange between mother and developing embryo. Here we show that α2-adrenoceptors, which are activated by adrenaline and noradrenaline, are important regulators of placental structure and function. Mice with deletions in the genes encoding α2A-, α2B- and α2C-adrenoceptors died between embryonic days 9.5 and 11.5 from a severe defect in yolk-sac and placenta development. In wildtype placentae, α2-adrenoceptors are abundantly expressed in giant cells, which secrete angiogenic factors to initiate development of the placental vascular labyrinth. In placentae deficient in α2A-, α2B- and α2C-adrenoceptors, the density of fetal blood vessels in the labyrinth was markedly lower than normal, leading to death of the embryos as a result of reduced oxygen and nutrient supply. Basal phosphorylation of the extracellular signal–regulated kinases ERK1 and ERK2 was also lower than normal, suggesting that activation of the mitogen-activated protein kinase (MAP kinase) pathway by α2-adrenoceptors is required for placenta and yolk-sac vascular development. Thus, α2-adrenoceptors are essential at the placental interface between mother and embryo to establish the circulatory system of the placenta and thus maintain pregnancy.

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Figure 1: Embryonic death in mice deficient in α2A-, α2B- and α2C-adrenoceptors.
Figure 2: Placental defects in mice deficient in α2A-, α2B- and α2C-adrenoceptors.
Figure 3: Normal development of embryos deficient in α2-adrenoceptors until day E10.5.
Figure 4: Expression of α2-adrenoceptor subtypes in the placenta on day E10.5.
Figure 5: Phosphorylation of ERK1 and ERK2 in placenta and yolk sac by α2-adrenoceptors on day E10.5.
Figure 6: Immunohistochemical detection of ERK1, ERK2 and phospho-ERK in mouse placenta at day E10.5.

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Acknowledgements

We thank N. Schumacher, C. Arnolt, M. Babl and G. Wolz-Curtaz for technical assistance, and D. Drenckhahn for drawing our attention to abnormalities in the development of embryonic blood vessels in the placenta. This study was supported by the Deutsche Forschungsgemeinschaft.

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  1. Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, Würzburg, 97078, Germany

    Melanie Philipp, Marc E. Brede, Kerstin Hadamek, Martin J. Lohse & Lutz Hein

  2. Theodor-Boveri-Institut für Biowissenschaften, Universität Würzburg, Am Hubland, Würzburg, 97074, Germany

    Manfred Gessler

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Correspondence to Lutz Hein.

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Philipp, M., Brede, M., Hadamek, K. et al. Placental α2-adrenoceptors control vascular development at the interface between mother and embryo. Nat Genet 31, 311–315 (2002). https://doi.org/10.1038/ng919

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