REPRODUCTION REVIEW Regulation of vascular growth and function in the human placenta Focus on Vascular Function in Female Reproduction G J Burton, D S Charnock-Jones 1 and E Jauniaux 2 Centre for Trophoblast Research and Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK, 1 Centre for Trophoblast Research and Department of Obstetrics and Gynaecology, and the National Institute of Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, CB2 2SW, UK and 2 Academic Department of Obstetrics and Gynaecology, Institute for Women’s Health, University College London, WC1E 6HX, London, UK Correspondence should be addressed to G J Burton; Email: gjb2@cam.ac.uk Abstract During the course of 9 months, the human placenta develops into a highly vascular organ. Vasculogenesis starts during the third week post-conception. Hemangioblastic cell cords differentiate in situ from mesenchymal cells in the villous cores, most probably under the influence of vascular endothelial growth factor (VEGFA) secreted by the overlying trophoblast. The cords elongate through proliferation and cell recruitment, and connect with the vasculature of the developing fetus. A feto-placental circulation starts around 8 weeks of gestation. Elongation of the capillaries outstrips that of the containing villi, leading to looping of the vessels. The obtrusion of both capillary loops and new sprouts results in the formation of terminal villi. Branching and non-branching angiogenesis therefore play key roles in villous morphogenesis throughout pregnancy. Maternal circulating levels of VEGFA and placental growth factor varyacross normal pregnancy, and in complicated pregnancies. Determining the impact of these changes on placental angiogenesis is difficult, as the relationship between levels of factors in the maternal circulation and their effects on fetal vessels within the placenta remains unclear. Furthermore, the trophoblast secretes large quantities of soluble receptors capable of binding both growth factors, influencing their bioavailability. Villous endothelial cells are prone to oxidative stress, which activates the apoptotic cascade. Oxidative stress associated with onset of the maternal circulation, and with incomplete conversion of the spiral arteries in pathological pregnancies, plays an important role in sculpting the villous tree. Suppression of placental angiogenesis results in impoverished development of the placenta, leading ultimately to fetal growth restriction. Reproduction (2009) 138 895–902 Introduction The human placenta is a highly vascular organ. By the end of gestation, it has developed a capillary network that is w550 km in length and 15 m 2 in surface area (Burton & Jauniaux 1995). This network is essential for effective materno-fetal exchange, but also plays a key mechanistic role in the elaboration of the placental villous tree. Vasculogenesis and subsequent angiogen- esis are therefore of pivotal importance in placental development, and it is imperative that they are appropriately regulated. Failure to do so can lead to intrauterine fetal growth restriction and poor obstetric outcome. Morphological aspects of vascular development The first morphological evidence of vasculogenesis can be seen within the cores of mesenchymal villi at 18–20 days post-conception (pc), or at the end of the fourth week after the last menstrual period (LMP). Hemangioblastic cells differentiate in situ and form small clumps or cords of cells lying just beneath the trophoblastic epithelium. These precursor endothelial cells are united by either desmosomes or tight junctions, and the cords gradually acquire lumens and unite to form vessels (Dempsey 1972, Demir et al. 1989). The first signs of lumen formation are seen around 23 days pc, and immunohistochemical and morphological evi- dences suggest that apoptosis is involved in the process (Tertemiz et al. 2005). Early erythrocytes, still containing a nucleus, are often seen within the newly formed lumen, having differentiated from the inner aspect of the hemangioblastic cluster. The cords elongate through a This paper is one of four papers that form part of a special Focus Issue section on Vascular Function in Female Reproduction. The Guest Editor for this section was H N Jabbour, Edinburgh, UK. q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-09-0092 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 06/15/2020 10:59:01AM via free access