The effects of human chorionic gonadotrophin, progesterone and oestradiol on trophoblast function Jessie Z.-J. Chen, May H. Wong, Shaun P. Brennecke, Rosemary J. Keogh ⇑ Department of Peinatal Medicine Pregnancy Research Centre and University of Melbourne Department of Obstetrics and Gynaecology, Royal Women’s Hospital, Parkville, Victoria, Australia article info Article history: Received 13 December 2010 Received in revised form 23 May 2011 Accepted 24 May 2011 Available online 1 June 2011 Keywords: Human chorionic gonadotrophin Invasion Migration Oestradiol Progesterone Trophoblast abstract Remodelling of the uterine vasculature during the first trimester of human pregnancy requires invasion of trophoblast from the placenta into decidual spiral arterioles. The pregnancy-associated hormones human chorionic gonadotropin (hCG), progesterone (P 4 ) and oestradiol (E 2 ) are present at high concen- trations at the maternal–fetal interface during the remodelling period and thus may contribute to the regulation of trophoblast movement. This study examined the effects of these hormones on trophoblast functions. HTR8/SVneo cells were treated with hCG (5–100 mIU/mL), P 4 (20 nM–20 lM) or E 2 (0.07– 734 nM). hCG significantly stimulated migration and MMP-9 activity but did not affect cell numbers. P 4 significantly inhibited migration, MMP-2 and -9 activity and reduced cell numbers. E 2 had no effect on migration, MMP activity or cell numbers. We conclude that hCG and P 4 , but not E 2 , play direct roles in controlling trophoblast invasion, acting as positive and negative stimuli respectively to regulate tro- phoblast movement during vascular remodelling in early pregnancy. Ó 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction A critical event early in human pregnancy is the transformation of the uterine spiral arterioles to create a high flow, low resistance vasculature. This is essential to maintain sufficient blood flow to the placenta to meet the oxygen and nutrient demands of the developing feto-placental unit. Trophoblast cells originating from the placenta invade into the maternal vessels, migrate along the spiral arterioles and initiate the remodelling process (Pijnenborg et al., 2006). Vessel transformation is characterised by loss of the endothelial lining and the smooth muscle layer that normally sur- rounds the vessels (Ashton et al., 2005; Harris et al., 2006; Keogh et al., 2007) and the integration of the invading trophoblast into the vessel walls (Brosens et al., 2002). Shallow or incomplete trophoblast invasion with limited vessel remodelling has been associated with complications of human pregnancy such as pre- eclampsia and fetal growth restriction (Brosens et al., 2002; Kaufmann et al., 2003). Gaining an understanding of the mecha- nisms that control trophoblast invasion will thus help to identify the defects in the process that contribute to the pathogenesis of such pregnancy complications. The trophoblast cells that carry out the remodelling process are known as extravillous trophoblast (EVT) and are characterised by a gain of invasive ability. This phenotypic change enables them to transition away from the tips of the placental villi and migrate into the maternal tissue (Duc-Goiran et al., 1999; Espinoza et al., 2006; Kaufmann et al., 2003). In order to become invasive, EVT must be- gin to secrete matrix metalloproteinases (MMPs) (Espinoza et al., 2006; Kaufmann et al., 2003). Acquisition of the ability to express the gelatinases MMP-2, MMP-9 and MMP-12 (Cohen et al., 2006; Harris et al., 2010) confers EVT with the capacity to degrade elas- tin, collagens and laminin, thus enabling them to invade through the extracellular matrix of the uterine decidual stroma and inte- grate into the walls of the spiral arterioles. The remodelling process commences early in the first trimester of pregnancy, with evidence of EVT in decidual vessels from around 8 weeks of gestation (Cartwright et al., 2010). The invasion of EVT into the spiral arterioles continues into the second trimester before ceasing at around 16–20 weeks of gestation with cells invading as deep as the first third of the myometrium (Kaufmann et al., 2003; Pijnenborg et al., 2006). EVT proliferation, migration and invasion are regulated by the complex interplay of growth factors, cyto- kines, endocrine factors, oxygen concentrations and haemodynam- ics at the maternal–fetal interface. These act both temporally and spatially to initially promote and then limit the extent of EVT inva- sion (Duc-Goiran et al., 1999; Red-Horse et al., 2004). Hormones produced by the placenta in particular are obvious candidates to be central regulators of vessel remodelling as they are present in high concentrations at the maternal–fetal interface where EVT invasion is initiated. There are however, no comprehensive studies 0303-7207/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2011.05.034 ⇑ Corresponding author at: Royal Women’s Hospital, Locked Bag 300, Corner Grattan Street and Flemington Road, Parkville 3052, Victoria, Australia. Tel.: +61 3 8345 3749, fax: +61 3 8345 3746. E-mail address: rosemary.keogh@thewomens.org.au (R.J. Keogh). Molecular and Cellular Endocrinology 342 (2011) 73–80 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce