An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

The Emerging Role of the Prokineticins and Homeobox Genes in the Vascularization of the Placenta: Physiological and Pathological Aspects

“…Recent studies from our own group and from others demonstrated that increased expression of EG-VEGF is associated with PE and FGR development (Hoffmann et al, 2006;Alfaidy, 2016;Inan et al, 2018). Our group also demonstrated that the concentration of EG-VEGF is significantly increased in both pathologies (Hoffmann et al, 2006;Murthi et al, 2015;Alfaidy, 2016). More recently, a study confirmed the increase in EG-VEGF levels in PE and proposed this factor as a biomarker for the diagnosis of PE patients (Inan et al, 2018).…”

“…In particular, EG-VEGF up-regulated the following homeobox genes, HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9, and HOXD11, while downregulating the expression of NKX 3.1. Further investigations using an in vitro model of trophoblast cells, we demonstrated that reduced NKX3.1 expression significantly enhanced premature differentiation and apoptosis in the syncytiotrophoblast cell line, the BeWo, while significantly reduced migration and invasive potential of the HTR8-SV neo cells (Murthi et al, 2015). This study was the first to demonstrate that the new placental angiogenic factor exhibits part of its effects on trophoblast invasion and differentiation through the NKX3.1 homeobox gene.…”

“…In 2015, our group demonstrated that the canonical member of the prokineticin family, EG-VEGF, controls homeobox genes expression in normal human placenta and in placenta from FGR pregnancies (Murthi et al, 2015). This regulation was observed in whole placenta explants, including endothelial, stroma and trophoblast cells.…”

“…Recent studies from our group provided evidence for the direct role of a new placental angiogenic called prokineticin 1 (PROK1) in normal and FGR pregnancies (Hoffmann et al, 2006(Hoffmann et al, , 2009Brouillet et al, 2012bBrouillet et al, , 2013bMurthi et al, 2015;Sergent et al, 2016). Due to its similarities of action with VEGF (LeCouter et al, 2001), PROK1 is also called as endocrine gland derived-vascular endothelial growth factor (EG-VEGF).…”

“…Ongoing validations of the newly discovered EG-VEGF-regulated homeobox genes should bring more insights into the role of these homeobox genes in the control of angiogenic processes at both intra-villi and extra-villi sites, throughout human pregnancy, Figure 1. Hoffmann et al, 2006Hoffmann et al, , 2009Brouillet et al, 2012aBrouillet et al, ,b, 2013bHolloway et al, 2014;Garnier et al, 2015;Murthi et al, 2015;Traboulsi et al, 2015Traboulsi et al, , 2017Sergent et al, 2016 HLX, DLX3, DLX4, MSX2, GAX,TLX1,TLX2 Murthi et al, 2007Murthi et al, , 2008Rajaraman et al, 2008Rajaraman et al, , 2010Chui et al, 2013;Liang et al, 2016;Novakovic et al, 2017;Harris et al,…”