Abstract
Idiopathic fetal growth restriction (FGR) is frequently associated with placental insufficiency. Previous reports have provided evidence that endocrine gland-derived vascular endothelial growth factor (EG-VEGF), a placental secreted protein, is expressed during the first trimester of pregnancy, controls both trophoblast proliferation and invasion, and its increased expression is associated with human FGR. In this study, we hypothesize that EG-VEGF-dependent changes in placental homeobox gene expressions contribute to trophoblast dysfunction in idiopathic FGR. The changes in EG-VEGF-dependent homeobox gene expressions were determined using a homeobox gene cDNA array on placental explants of 8-12 wks gestation after stimulation with EG-VEGF in vitro for 24 h. The homeobox gene array identified a greater-than-five-fold increase in HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9 and HOXD11, while NKX 3.1 showed a greater-than-two-fold decrease in mRNA expression compared with untreated controls. Homeobox gene NKX3.1 was selected as a candidate because it is a downstream target of EG-VEGF and its expression and functional roles are largely unknown in control and idiopathic FGR-affected placentae. Real-time PCR and immunoblotting showed a significant decrease in NKX3.1 mRNA and protein levels, respectively, in placentae from FGR compared with control pregnancies. Gene inactivation in vitro using short-interference RNA specific for NKX3.1 demonstrated an increase in BeWo cell differentiation and a decrease in HTR-8/SVneo proliferation. We conclude that the decreased expression of homeobox gene NKX3.1 downstream of EG-VEGF may contribute to the trophoblast dysfunction associated with idiopathic FGR pregnancies.
Highlights
Fetal growth restriction (FGR), known as intrauterine growth restriction, is a pregnancy complication in which a fetus fails to reach its genetically determined growth potential in utero
We have recently shown that endocrine gland–derived vascular endothelial growth factor (EG-VEGF) and its receptors are highly expressed in the human placenta during the first-trimester of pregnancy, with the highest expression found in the ST; that its expression is upregulated by hypoxia; and that its circulating levels are significantly higher during early pregnancy and in pregnancy pathologies including FGR and pulmonary embolism (PE) [16,17,18,19]
Using BeWo cells that mimic syncytiotrophoblast cells, we demonstrated that EG-VEGF might have a direct effect on the regulation of NKX3.1 expression, since both PROKR1 and PROKR2 antagonists abolished the decrease in NKX3.1 expression observed under hypoxia, a condition that mimics FGR and increases EG-VEGF production
Summary
Fetal growth restriction (FGR), known as intrauterine growth restriction, is a pregnancy complication in which a fetus fails to reach its genetically determined growth potential in utero. Impairment in fetal development and growth in utero has been associated with lifelong adverse health sequelae, including diabetes and cardiovascular diseases [1,2], understanding the molecular mechanism of human FGR is of utmost importance. The ST layer plays a key role throughout pregnancy It is the site for several important placental functions, including nutrient and ion exchange and the synthesis of hormones required for fetal growth and development [7,8]. A dysfunction in CTB differentiation and proliferation leads to deficient EVCT invasion and ST apoptosis, both hallmarks of pregnancy pathologies, including human idiopathic FGR [6,9]
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