Ontogeny of Placental Structural Development and Expression of the Renin–Angiotensin System and 11b-HSD 2 Genes in the Rabbit A.M. McArdle a , K.M. Denton a , D. Maduwegedera a , K. Moritz b , R.L. Flower a , C.T. Roberts c, * a Department of Physiology, Monash University, Melbourne, Australia b School of Biomedical Sciences, University of Queensland, Brisbane, Australia c Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia 5005, Australia article info Article history: Accepted 14 April 2009 Keywords: Pregnancy Placenta Renin–angiotensin system Rabbit abstract Common pregnancy complications are associated with impaired placental development. This study aimed to characterise the ontogeny of structural correlates of rabbit placental function, its expression of genes encoding components of the renin–angiotensin system (RAS), as well as 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD 2 ) mRNA since these are known to be expressed by the placenta and are associated with pregnancy complications, including preeclampsia and intrauterine programming. Placentae were collected at gestational age (GA) 14, 21 and 28 (term ¼ 32 days). Gene expression was analysed using real time PCR and placental structures were quantified via image analyses. The volume densities and volumes of trophoblast, fetal capillaries, maternal blood space, surface density and surface area of trophoblast all progressively increased, while the arithmetic mean barrier thickness of tropho- blast decreased across gestation. Maternal plasma renin activity (PRA) was positively correlated with volumes of trophoblast and maternal blood space, surface density and surface area of trophoblast. Placental renin mRNA declined (Y62%; P < 0.01) across gestation and was negatively correlated with maternal PRA (GA0), fetal and placental weights, placental angiotensin type 1 and 2 receptors (AT 1 R and AT 2 R) mRNA and volume of trophoblast. AT 1 R mRNA expression was increased by 92% (P < 0.001) across gestation. AT 2 R mRNA expression was w81% (P < 0.01) greater at GA14 compared to GA21. Placental 11b- HSD 2 mRNA expression was w74% greater (P < 0.01) at GA21 than GA14, but by GA28 was similar to that at GA14. These data show that changes in placental gene expression are associated with key events in placental and fetal development, indicating that the rabbit provides a good model for investigations of pregnancy perturbations that alter the RAS or programme the fetus. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction The placenta is a highly specialised organ that plays an essential role in fetal growth and development and in maternal adaptation to pregnancy [1,2]. Common pregnancy complications are associated with poor placental development, including inad- equate trophoblast invasion and altered angiogenesis [3]. In addition, the quality of the maternal adaptation to pregnancy is also known to contribute to pregnancy success. Current evidence suggests that alterations to essential nutritional and endocrine functions of the placenta may occur in response to changes in the maternal environment [2]. The placenta forms the interface between the fetus and the mother. Therefore changes in the maternal environment may alter placental development and function [2]. These placental changes may further contribute to an adverse intrauterine milieu and increase the risk of the develop- ment of adult diseases, including cardiovascular disease in offspring, a phenomenon known as intrauterine programming [2,4]. Good animal models of placental differentiation and growth are important to enable investigation into the causes and mechanisms involved in intrauterine programming and aberrant maternal adaptation to pregnancy. We have previously shown in a rabbit model of chronic maternal hypertension that offspring have increased arterial pressure as adults [5]. The rabbit as a model for the study of reproductive function and development has many advantages. The uterus is duplex [6] allowing controlled indepen- dent experiments in each uterine horn. Rabbit placentation is similar to that of humans as both have invasive discoid hemochorial placentas, although the rabbit placenta is hemodichorial while that of the human placental is hemomonochorial [7]. However the pattern of feto-maternal interdigitation at the placental exchange * Corresponding author. Tel.: þ61 8 83033118; fax: þ61 8 83034099. E-mail address: claire.roberts@adelaide.edu.au (C.T. Roberts). Contents lists available at ScienceDirect Placenta journal homepage: www.elsevier.com/locate/placenta 0143-4004/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.placenta.2009.04.006 Placenta 30 (2009) 590–598