Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Weiss, E.
Inflammatory memory of fetal endothelial cells: Intrauterine programming by maternal metabolism and influence of fetal sex
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 113
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Gauster Martin
- Hiden Ursula
- Tokic Silvija
- Altmetrics:
- Abstract:
- The placenta is a fetal organ that enables an exchange between the maternal and fetal circulations. Disturbances herein result in severe implications for fetal development and postnatal health. A major role is attributed to the placental vasculature with special emphasis on endothelial cells. While cardiovascular risk factors, such as overweight or elevated blood glucose, adversely affect endothelial function in adults, they can transmit from the mother to the fetus during pregnancy. Furthermore, a sexual dimorphism in adult risk for endothelial dysfunction and cardiovascular diseases exists. Thus, we hypothesized that maternal metabolism determines fetal endothelial function via intrauterine programming in a sex-specific manner. We employed fetal endothelial cells isolated from placenta (fpAEC; feto-placental arterial endothelial cells), umbilical cord (HUVEC; human umbilical vein endothelial cells) and umbilical cord blood (ECFC; endothelial colony forming cells). First, we analysed the effect of maternal metabolic parameters and of fetal sex on initial ECFC colony outgrowth, as a crucial determinant of endothelial progenitor function. Our data indeed revealed a sexual dimorphism in ECFC function already in the perinatal period. While male offspring cells exhibited faster outgrowth than female offspring cells, their outgrowth dynamics were susceptible towards maternal fasting plasma glucose levels. Higher glycemia within a healthy, non-diabetic range prolonged the time until ECFC outgrowth. Secondly, we investigated the effect of maternal overweight on fpAEC. To do so, we measured the expression of MME (membrane metalloendopepidase), an enzyme that cleaves several peptides involved in vascular tone regulation. Interestingly, we identified reduced MME levels in fpAEC and in cord blood of overweight mothers, highlighting the effect of maternal metabolism on fetal and neonatal endothelial function. Finally, we investigated the role of inflammatory processes in fetal programming. To analyse endothelial response to inflammation and memory thereof, we profiled the gene expression of ECFC and HUVEC in response to stimulation with bacterial and viral mimics. While similar transcriptional remodelling was induced in both, some cell type specific expression patterns were observed. These inflammatory responses were barely related to modifications in DNA methylation, suggesting other epigenetic mechanisms to be involved. We then showed that the initial stimulation induced immune memory, altering the cellular response to a microbial re-challenge. This inflammatory memory trait of fetal endothelial cells may explain their programming by immuno-metabolic changes in utero.