Regulatory mechanisms of decidual gene expression linking absence of corpus luteum with preeclamptic pregnancies

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Preeclampsia is a hypertensive disorder of pregnancy with impaired decidualization as an important contributor to the pathogenesis of the disease. Assisted reproductive technology (ART) procedures are increasingly utilized worldwide and associated with a significantly higher incidence of preeclampsia. Our recent and novel data show that this is particularly true for ART conceptions occurring in the absence of a corpus luteum (CL), e.g. in frozen embryo transfers (FET) performed in a programmed cycle. Additionally, those women who conceived without a CL exhibit impaired vascular function in early pregnancy. Interestingly, concentrations of the vasodilatory peptide hormone relaxin which is almost exclusively released by the CL in humans are undetectable in these women. How the lack of a CL and the CL hormone relaxin adds to the increased preeclampsia risk remains largely unknown and will be the focus of the proposed project. The overarching hypothesis supported by our published data and further preliminary work suggests, that the adverse maternal circulating environment in women lacking a CL induces biologic modifications which adversely affect decidualization paving the way for the development of adverse pregnancy outcomes, e.g. preeclampsia. The project will begin to close this knowledge gap by exploring how decidualization is compromised in the absence of a CL by investigating which factors impact specific gene expression changes associated with preeclampsia and how gene expression can be rescued utilizing endometrial and placental tissue as well as in vitro models. In different work packages, we will1. Compare transcriptomic profiles of decidualized endometrium derived from natural cycle FET and programmed cycle FET and to correlate the results with transcriptomic abnormalities to be known of subjects with preeclampsia.2. Determine splicing patterns and identify specific alternative splice-variants of decidualized endometrium derived from natural cycle FET and programmed cycle FET.3. Determine long-non-coding (lnc) RNAs and identify specific lnc RNA profiles of decidualized endometrium derived from natural cycle FET and programmed cycle FET. 4. Recapitulate gene expression changes in vitro, to investigate their functional consequences in HESC systems and to develop methods to restore functionality of gene expression.These data will provide novel insight into mechanisms involved in preeclampsia pathophysiology and provide the basis for the development of approaches to restore decidual homeostasis of women at risk as early as in the periconceptional period. Understanding the underlying mechanisms could ultimately lead to practical changes in clinical practice (e.g. more frequent use of protocols creating a CL or supplementation of CL products) and a reduction of adverse pregnancy outcomes which arise on the basis of a disturbed decidualization.