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bioRxiv · 10.1101/275503

A mouse model of maternal obesity leads to uterine natural killer (uNK) cell activation and uterine artery remodeling defects

Baltayeva, J.·Castellana, B.·Mara, D.·Christians, J. K.·Beristain, A. G.
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Abstract

Maternal obesity associates with multiple adverse reproductive outcomes, negatively affecting the health and survival of both the mother and the fetus. The contributory effects of obesity on adipose-derived immune changes have been well established, however the mechanisms that link obesity to pregnancy complications remain unclear. Proper development of the placenta and establishment of utero-placental vasculature is essential in early pregnancy to allow for optimal fetal growth and survival. Uterine immune cells, particularly uterine natural killer (uNK) cells, play fundamental roles in promoting these events. Using an obesogenic high-fat/high-sucrose (HFD) mouse model of maternal obesity, uNK cells and placenta/uterine vascular remodeling were examined at gestational days (Gd) 10.5 and 14.5 of pregnancy. While mice fed a HFD 13 weeks prior to pregnancy significantly gained more weight than control mice fed a low-fat/no-sucrose diet (LFD), fetal survival was not different in either diet. At Gd 10.5, HFD had no effect on total uNK proportions, nor did it affect proportions of distinct CD122+/CD49a tissue resident or CD122+/DX5+ conventional uNKs. However, HFD resulted in increased proportions of NCR1+ uNK and overall heightened uNK activity. Moreover, HFD resulted in impairments in uterine vascular remodeling at Gd10.5. By Gd14.5, uterine artery defects were no longer observed and placental structure was comparable between HFD and LFD mice. Gene analysis of IFN{gamma}, TNF and VEGFA in Gd10.5 uNK indicated that, while not significant, a HFD leads to subtle alterations in uNK cytokine gene expression. These findings show that HFD in mice results in changes in uNK biology and temporary uterine artery remodeling impairments. Further, this work establishes insight into the cellular changes occurring in early pregnancy as a result of HFD exposure.

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Baltayeva, J., Castellana, B., Mara, D., Christians, J. K., Beristain, A. G.. 2018-03-03. A mouse model of maternal obesity leads to uterine natural killer (uNK) cell activation and uterine artery remodeling defects. https://doi.org/10.1101/275503

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