Study of the mechanisms underlying the salutary effects of Heme Oxygenase-1 in implantation, placentation and fetal growth using a mouse model and in vitro approaches. Participation of carbon monoxide in the preparation of the murine uterine microenvironment for pregnancy.

• Applicant: Professorin Dr. Ana Claudia Zenclussen
• Subject Area: Reproductive Medicine, Urology ; Gynaecology and Obstetrics
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277699676

Normal pregnancy is a physiological state characterized by the occurrence of different processes taking place at different stages, each of them unique. Pregnancy begins with the fertilization of the ovum, followed by implantation of the blastocyst in the maternal uterus. To implant, the blastocyst needs to adhere to the endometrium so that it can be provided with oxygen and nutrients. For these dramatic changes to occur, tissue remodeling and inflammatory processes in the uterus are required. However, the ablation of immunosuppressive molecules is detrimental, so that it can be assumed that both, inflammatory and anti-inflammatory pathways are required. Heme oxygenase (HO) is a ubiquitous enzyme that catalyzes the initial and rate limiting step in the oxidative degradation of heme to bilirubin. CO and biliverdin, both generated via the catabolism of heme by the isoform HO-1, are potent immunosupressors which induce tolerance against allografted organs. We have recently shown that HO-1 is critical for pregnancy success as it determines implantation, placentation and intrauterine fetal survival. This is mainly mediated by the HO-1 metabolite CO. After implantation occured and while placentation is taking place, a period of immune tolerance must exist that allows the half-foreign embryo to grow without being attacked by the maternal immune system. HO-1 modulates the maternal immune system to allow tolerance towards the growing fetus by affecting the function of dendritic cells and regulatory T cells. HO-1 is therefore a central regulator of pregnancy as it critically interferes with the important steps of implantation, placentation, embryonic and fetal development and immune tolerance. Thus, the study of mechanisms underlying HO-1-protective functions during pregnancy is clinically very relevant. The present project deals with HO-1-associated mechanisms that allow implantation to occur and focuses on the HO-1-modulated changes in the uterine microenvironment that are necessary for the embryo to implant and grow. The project further aims to determine the importance of HO-1 and CO in allowing a proper blood flow that ensures a correct placentation and fetal support.

• DFG Programme: Research Grants
• Major Instrumentation: Ultraschallgerät für Mäuse, Dopplergerät
• Instrumentation Group: 3900 Ultraschall-Diagnostikgeräte
• Co-Investigator: Privatdozentin Dr. Anne Schumacher