Molecular Regulation of Human Placental Growth Factor (PlGF) Gene Expression in Placental Villi and Trophoblast Cells is Mediated via the Protein Kinase A Pathway
- 6 December 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Reproductive Sciences
- Vol. 18 (3), 219-228
- https://doi.org/10.1177/1933719110389337
Abstract
Cyclic 3',5'-adenosine monophosphate (cAMP) is a critical second messenger for human trophoblasts and regulates the expression of numerous genes. It is known to stimulate in vitro the fusion and differentiation of BeWo choriocarcinoma cells, which acquire characteristics of syncytiotrophoblasts. A DNA microarray analysis of BeWo cells undergoing forskolin-induced syncytialization revealed that among the induced genes, placental growth factor (PlGF) was 10-fold upregulated. We verified this result in two choriocarcinoma cell lines, BeWo and JEG-3, and also in first trimester placental villous explants by quantifying PlGF mRNA (real time PCR) and PlGF protein secreted into the supernatant (ELISA). Similar effects were noted for vascular endothelial growth factor (VEGF) mRNA and protein expression. Treatment with cholera toxin and the use of a specific inhibitor of protein kinase A (PKA) blocked these effects, indicating that the cAMP/PKA pathway is responsible for the cAMP-induced upregulation of PlGF and that one or more G protein coupled receptor(s) was involved. We identified two functional cAMP responsive elements (CRE) in the PlGF promoter and demonstrated that the CRE binding protein, CREB, contributes to the regulation of PlGF gene expression. We speculate that defects in this signaling pathway may lead to abnormal secretion of PlGF protein as observed in the pregnancy-related diseases preeclampsia and intrauterine growth restriction.Keywords
This publication has 44 references indexed in Scilit:
- The Functional Role of the Renin–Angiotensin System in Pregnancy and PreeclampsiaPlacenta, 2008
- HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteumMolecular Human Reproduction, 2008
- Vascular Actions of Estrogens: Functional ImplicationsPharmacological Reviews, 2008
- Glial Cell Missing 1 Regulates Placental Growth Factor (PGF) Gene Transcription in Human Trophoblast1Biology of Reproduction, 2008
- Steroid Hormones and Uterine Vascular Adaptation to PregnancyReproductive Sciences, 2008
- The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrityJCI Insight, 2008
- Mechanisms in the regulation of aromatase in developing ovary and placentaThe Journal of Steroid Biochemistry and Molecular Biology, 2007
- Soluble Endoglin and Other Circulating Antiangiogenic Factors in PreeclampsiaNew England Journal of Medicine, 2006
- Stimulation of GCMa and syncytin via cAMP mediated PKA signaling in human trophoblastic cells under normoxic and hypoxic conditionsFEBS Letters, 2005
- Adrenomedullin, a New Vasoactive Peptide, Is Increased in PreeclampsiaHypertension, 1998