ORIGINAL PAPER Journal of Pathology J Pathol 2011; 225: 293–304 Published online 8 July 2011 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.2946 Haem oxygenase-1 dictates intrauterine fetal survival in mice via carbon monoxide Maria Laura Zenclussen, 1 Pablo Ariel Casalis, 2 Tarek El-Mousleh, 1 Sofia Rebelo, 3 Stefanie Langwisch, 1 Nadja Linzke, 1 Hans-Dieter Volk, 4,5 Stefan Fest, 6 Miguel Parreira Soares 3 and Ana Claudia Zenclussen 1 * 1 Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Gerhart-Hauptmann-Strasse 35, 39108, Magdeburg, Germany 2 Department of Neurosurgery, Charit´ e, Universit¨ atsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany 3 Instituto Gulbenkian de Ciˆ encia, Rua da Quinta Grande 6, P2780-156, Oeiras, Portugal 4 Institute of Medical Immunology, Charit´ e Universit¨ atsmedizin, Charit´ eplatz 1, 10115 Berlin, Germany 5 Berlin-Brandenburg Center for Regenerative Therapies, Augustenburgerplatz 1, 13353, Berlin, Germany 6 Pediatric Immunotherapies, Department of Pediatrics and Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University, Leipziger Strasse 44, 39120, Magdeburg, Germany *Correspondence to: Ana Claudia Zenclussen, Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Gerhart-Hauptmann-Strasse 35, 39108, Magdeburg, Germany. e-mail: ana.zenclussen@med.ovgu.de Abstract Pregnancy establishment implies the existence of a highly vascularized and transient organ, the placenta, which ensures oxygen supply to the fetus via haemoproteins. Haem metabolism, including its catabolism by haem oxygenase-1 (HO-1), should be of importance in maintaining the homeostasis of haemoproteins and controlling the deleterious effects associated with haem release from maternal or fetal haemoglobins, thus ensuring placental function and fetal development. We demonstrate that HO-1 expression is essential to promote placental function and fetal development, thus determining the success of pregnancy. Hmox1 deletion in mice has pathological consequences for pregnancy, namely suboptimal placentation followed by intrauterine fetal growth restriction (IUGR) and fetal lethality. These pathological effects can be mimicked by administration of exogenous haem in wild-type mice. Fetal and maternal HO-1 is required to prevent post-implantation fetal loss through a mechanism that acts independently of maternal adaptive immunity and hormones. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of haem catabolism by HO-1 that restores placentation and fetal growth. In a clinical relevant model of IUGR, CO reduces the levels of free haem in circulation and prevents fetal death. We unravel a novel physiological role for HO-1/CO in sustaining pregnancy which aids in understanding the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy pathologies. Copyright  2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: haem; pregnancy; haem oxygenase; carbon monoxide; placentation; intrauterine growth restriction Received 13 January 2011; Revised 18 May 2011; Accepted 25 May 2011 No conflicts of interest were declared. Introduction Haem oxygenases (HO) catalyse the first and rate- limiting step in haem catabolism towards biliverdin, carbon monoxide (CO), and free iron [1]. The stress- responsive HO-1 isoform, encoded by the Hmox1 gene, is cytoprotective [2] and exerts anti-inflammatory effects [3,4] while modulating cell proliferation [5]. HO-1 prevents tissue damage and regulates innate as well as adaptive immunity in a manner that sup- presses the pathogenesis of a broad range of immune- mediated inflammatory diseases [4,6,7]. The cytopro- tective and immunoregulatory effects of HO-1 are ablated when its enzymatic activity is inhibited phar- macologically, being restored when CO is supplied exogenously [3,8–10]. Consequently, CO mediates to a large extent the salutary effects of HO-1; however, other products of haem catabolism by HO-1, ie iron and biliverdin, might act in a similar manner. A few Hmox1 null (Hmox1 −/− ) mice, obtained by mat- ing Hmox1 +/− mice, survive to adulthood. Surviv- ing Hmox1 −/− female mice are reported as infer- tile [11–13]. The placenta is a unique organ which ensures oxygen supply to the fetus via haemopro- teins [14]. Thus, haem metabolism, including its catabolism by HO-1, should play an important role in maintaining the homeostasis of haemoproteins, ensur- ing placental development and function. Expression of HO-1 is highly induced during human, rat, and mouse pregnancy, namely in placental trophoblasts [14–17]. Reduced HO-1 levels are associated with human and murine miscarriages [16,18] and pre- eclampsia, the most severe pathological complica- tion of pregnancy [19]. HO-1 induction supports Copyright  2011 Pathological Society of Great Britain and Ireland. J Pathol 2011; 225: 293–304 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com