Role of EG-VEGF in human placentation: Physiological  and pathological implications.
Pre-eclampsia (PE), the major cause of maternal morbidity and mortality, is thought to be caused by shallow invasion of the maternal decidua by extravillous trophoblasts (EVT). Data suggest that a fine balance between the expressions of pro- and anti-invasive factors might regulate EVT invasiveness. Recently, we showed that the expression of the new growth factor endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is high in early pregnancy but falls after 11 weeks, suggesting an essential role for this factor in early pregnancy. Using human villous explants and HTR-8/SVneo, a first trimester extravillous trophoblast cell line, we showed differential expression of EG-VEGF receptors, PKR1 and PKR2, in the placenta and demonstrated that EG-VEGF inhibits EVT migration, invasion and tube-like organisation. EG-VEGF inhibitory effect on invasion was supported by a decrease in matrix metalloproteinase (MMP)-2 and MMP-9 production. Interference with PKR2 expression, using specific siRNAs, reversed the EG-VEGF-induced inhibitory effects. Furthermore, we determined EG-VEGF circulating levels in normal and PE patients. Our results showed that EG-VEGF levels were highest during the first trimester of pregnancy and decreased thereafter to non-pregnant levels. More important, EG-VEGF levels were significantly elevated in PE patients compared with age-matched controls. These findings identify EG-VEGF as a novel paracrine regulator of trophoblast invasion. We speculate that a failure to correctly down-regulate placental expression of EG-VEGF at the end of the first trimester of pregnancy might lead to PE.
Hoffmann
Pascale
P
Institut National de la Santé et de la Recherche Médicale, Grenoble, France.|Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre Hospitalier Régional Universitaire de Grenoble, Département de Gynécologie, Obstétrique et Médecine de la Reproduction, Grenoble, France.
Saoudi
Yasmina
Y
Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Institut National de la Santé et de la Recherche Médicale, Grenoble, France.
Benharouga
Mohamed
M
Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.|Centre National de la Recherche Scientifique, Grenoble, France.
Graham
Charles H
CH
Department of Anatomy and Cell Biology, Queen's University, Kingston, Ontario, Canada.
Schaal
Jean-Patrick
JP
Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
Mazouni
Chafika
C
Département de Gynécologie, Obstétrique, Hôpital de la Conception, Marseille, France.
Feige
Jean-Jacques
JJ
Institut National de la Santé et de la Recherche Médicale, Grenoble, France.|Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
Alfaidy
Nadia
N
Institut National de la Santé et de la Recherche Médicale, Grenoble, France.|Commissariat à l'Energie Atomique, iRTSV, Grenoble, France.|Université Joseph Fourier, Grenoble, France.
D000328:Adult; D005260:Female; D006801:Humans; D010920:Placenta / Q000502:physiology* / Q000503:physiopathology; D011247:Pregnancy; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000502:physiology*
D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived