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An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible
Padma Murthi1,2, Sophie Brouillet3,4,5,6, Anita Pratt1
1Department of Perinatal Medicine Pregnancy Research Centre, The Royal Women's Hospital and The University of Melbourne Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Victoria, Australia.
Molecular Medicine (Cambridge, Mass.)
|July 25, 2015
Summary
Idiopathic fetal growth restriction (FGR) is linked to placental issues. Decreased expression of the homeobox gene NKX3.1, influenced by EG-VEGF, may cause trophoblast dysfunction in FGR pregnancies.
Area of Science:
- Reproductive biology
- Developmental biology
- Genetics
Background:
- Idiopathic fetal growth restriction (FGR) is often linked to placental insufficiency.
- Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is a placental protein involved in early pregnancy, trophoblast function, and FGR.
- The role of EG-VEGF-dependent homeobox gene expression in FGR-related trophoblast dysfunction requires further investigation.
Purpose of the Study:
- To investigate the hypothesis that EG-VEGF-dependent changes in placental homeobox gene expression contribute to trophoblast dysfunction in idiopathic FGR.
- To identify specific homeobox genes affected by EG-VEGF and examine the role of NKX3.1 in FGR placentae.
Main Methods:
- Placental explants from 8-12 weeks gestation were stimulated with EG-VEGF in vitro.
- Homeobox gene expression changes were analyzed using a cDNA array.
- Quantitative real-time PCR and immunoblotting were used to assess NKX3.1 mRNA and protein levels in FGR and control placentae.
- In vitro gene inactivation of NKX3.1 was performed using short-interference RNA in trophoblast cell lines.
Main Results:
- EG-VEGF stimulation significantly increased the expression of HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9, and HOXD11.
- EG-VEGF stimulation decreased NKX3.1 mRNA expression by over two-fold.
- Placentae from FGR pregnancies showed significantly decreased NKX3.1 mRNA and protein levels compared to controls.
- In vitro inactivation of NKX3.1 led to increased BeWo cell differentiation and decreased HTR-8/SVneo cell proliferation.
Conclusions:
- EG-VEGF influences the expression of multiple homeobox genes in the placenta.
- Decreased expression of the homeobox gene NKX3.1, a downstream target of EG-VEGF, is observed in idiopathic FGR.
- Reduced NKX3.1 expression may contribute to trophoblast dysfunction, impacting placental development and function in FGR pregnancies.
