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Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors

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Abstract

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor reported to be specific for endocrine tissues, including the placenta. Its biological activity is mediated via two G protein-coupled receptors, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). We have recently shown that (i) EG-VEGF expression peaks between the 8th and 11th weeks of gestation, (ii) its mRNA and protein levels are up-regulated by hypoxia, (iii) EG-VEGF is a negative regulator of trophoblast invasion and (iv) its circulating levels are increased in preeclampsia (PE), the most threatening pathology of pregnancy. Here, we investigated the regulation of the expression of EG-VEGF and its receptors by hCG, a key pregnancy hormone that is also deregulated in PE. During the first trimester of pregnancy, hCG and EG-VEGF exhibit the same pattern of expression, suggesting that EG-VEGF is potentially regulated by hCG. Both placental explants (PEX) and primary cultures of trophoblasts from the first trimester of pregnancy were used to investigate this hypothesis. Our results show that (i) LHCGR, the hCG receptor, is expressed both in cyto- and syncytiotrophoblasts, (ii) hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, (iii) hCG increases the release of EG-VEGF from PEX conditioned media, (iv) hCG effects are transcriptional and post-transcriptional and (v) the hCG effects are mediated by cAMP via cAMP response elements present in the EG-VEGF promoter region. Altogether, these results demonstrate a new role for hCG in the regulation of EG-VEGF and its receptors, an emerging regulatory system in placental development.

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Acknowledgments

We thank the staff of the Department of Gynecology/Obstetrics (Pr. J.P. Schaal) at the University Hospital of Grenoble for giving us access to human placentas. We acknowledge the following sources of funding: INSERM (U1036), University Joseph Fourier, Commissariat à l’Energie Atomique (DSV/iRTSV/BCI), the Région Rhône-Alpes (CIBLE-2008). S.B. was supported by doctoral scholarships from the French Ministry of Education and Research and from the Fondation pour la Recherche Médicale.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, Unité 1036, Laboratoire Biologie du Cancer et de l’Infection, Grenoble, France

    S. Brouillet, P. Hoffmann, A. Salomon, S. Chamboredon, J. J. Feige & N. Alfaidy

  2. Commissariat à l’Energie Atomique, iRTSV, Grenoble, France

    S. Brouillet, P. Hoffmann, S. Chauvet, A. Salomon, S. Chamboredon, M. Benharouga, J. J. Feige & N. Alfaidy

  3. Université Joseph Fourrier, Grenoble, France

    S. Brouillet, S. Chauvet, A. Salomon, M. Benharouga, J. J. Feige & N. Alfaidy

  4. Centre Hospitalier Régional Universitaire de Grenoble, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, Grenoble, France

    P. Hoffmann, F. Sergent & N. Alfaidy

  5. Centre National de la Recherche Scientifique, UMR 5249, Grenoble, France

    S. Chauvet & M. Benharouga

  6. INSERM U1036 iRTSV/BCI, CEA-G17, rue des Martyrs. 38054, Grenoble, Cedex 9, France

    N. Alfaidy

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  1. S. Brouillet
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  2. P. Hoffmann
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  9. N. Alfaidy
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Correspondence to N. Alfaidy.

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Brouillet, S., Hoffmann, P., Chauvet, S. et al. Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors. Cell. Mol. Life Sci. 69, 1537–1550 (2012). https://doi.org/10.1007/s00018-011-0889-x

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  • DOI: https://doi.org/10.1007/s00018-011-0889-x

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