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 microenvironm

正常妊娠是一种生理状态，其特征是在不同的阶段发生不同的过程，每个过程都是独特的。怀孕始于卵子受精，然后将胚泡植入母体子宫。为了植入，胚泡需要附着在子宫内膜上，以便为其提供氧气和营养。要发生这些戏剧性的变化，子宫中的组织重塑和炎症过程是必需的。然而，免疫抑制分子的消融是有害的，因此可以认为，炎症和抗炎两种途径都是必需的。血红素加氧酶(HO)是一种普遍存在的酶，催化血红素氧化降解为胆红素的起始步骤和限速步骤。CO和胆绿素都是通过异构体HO-1分解血红素而产生的，是诱导对同种移植器官耐受的有效免疫抑制剂。我们最近发现，HO-1对妊娠成功至关重要，因为它决定着床、胎盘和胎儿宫内存活率。这主要是由HO-1代谢物CO介导的。在植入后和胎盘形成期间，必须存在一段免疫耐受期，使半异体胚胎能够在不受母体免疫系统攻击的情况下生长。HO-1通过影响树突状细胞和调节性T细胞的功能来调节母体免疫系统，以允许对发育中的胎儿的耐受性。因此，HO-1是妊娠的中央调节因子，因为它严重干扰着床、胎盘、胚胎和胎儿发育以及免疫耐受等重要步骤。因此，研究孕期HO-1保护作用的机制具有重要的临床意义。本项目涉及允许着床发生的HO-1相关机制，并侧重于HO-1调节的子宫微环境变化，这些变化是胚胎植入和生长所必需的。该项目还旨在确定HO-1和CO在允许适当的血液流动以确保正确的胎盘和胎儿支持方面的重要性。

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.