EG-VEGF controls placental growth and survival in normal and pathological pregnancies: Case of fetal growth restriction (FGR)

Sophie Brouillet, P. Murthi, P Hoffmann, Joshua A Salomon, Frédéric Sergent, P. De Mazancourt, M. Dakouane-Giudicelli, M. N. Dieudonné, P. Rozenberg, D. Vaiman, S. Barbaux, Mohamed Benharouga, Jean-Jacques Feige, Nadia Alfaidy

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38 Citations (Scopus)

Abstract

Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([3H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.

Original languageEnglish
Pages (from-to)511-525
Number of pages15
JournalCellular and Molecular Life Sciences
Volume70
Issue number3
DOIs
Publication statusPublished - Feb 2013
Externally publishedYes

Keywords

  • Angiogenesis
  • EG-VEGF
  • FGR
  • Placenta
  • Prokineticin

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