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

Cell Mol Life Sci. 2013 Feb;70(3):511-25. doi: 10.1007/s00018-012-1141-z. Epub 2012 Sep 2.


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 ([(3)H]-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Female
  • Fetal Growth Retardation / metabolism*
  • Fetal Growth Retardation / pathology
  • Giant Cells / cytology
  • Homeodomain Proteins / metabolism
  • Humans
  • Placenta / cytology
  • Placenta / metabolism*
  • Placentation
  • Pregnancy
  • Pregnancy Trimester, First
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Transcription Factors / metabolism
  • Trophoblasts / cytology
  • Trophoblasts / metabolism
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / genetics
  • Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / metabolism*


  • HLX protein, human
  • Homeodomain Proteins
  • PROKR1 protein, human
  • PROKR2 protein, human
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Peptide
  • Recombinant Proteins
  • Transcription Factors
  • Vascular Endothelial Growth Factor, Endocrine-Gland-Derived