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Elevated Saturated Fatty Acids Attenuate Trophoblast Migration Via TLR Signaling Mechanisms
Author(s) -
Bradshaw Jessica L.,
Strong Luke B.,
Granger Joey P.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.865.15
Subject(s) - preeclampsia , trophoblast , medicine , endocrinology , albumin , inflammation , endothelial dysfunction , spiral artery , andrology , placenta , biology , fetus , pregnancy , genetics
Preeclampsia (PE) is characterized by the abrupt onset of high blood pressure, systemic inflammation, and widespread vascular dysfunction. Specifically, early onset PE is associated with attenuated trophoblast migration and improper spiral artery remodeling that leads to placental ischemia and release of inflammatory and anti‐angiogenic factors into the maternal circulation. A major risk factor for the development of preeclampsia is obesity; yet, the underlying mechanism that contributes to the increased risk of preeclampsia in obese patients is not clear. Circulating saturated fatty acids (SFAs) are elevated in obese and preeclamptic women and have been shown to stimulate inflammatory pathways by triggering toll‐like receptors (TLRs) and inflammatory responses. While SFAs are elevated in PE, it is unknown whether they contribute to the pathophysiology of preeclampsia. We hypothesized that elevated SFAs stimulate TLRs on trophoblast cells and attenuate trophoblast migration. To test this hypothesis, we cultured Bewo human trophoblasts with the SFAs palmitate (PAL), stearate (STE), or myristate (MYR) for 24 hours at concentrations mimicking SFA levels in preeclamptic (0.2 mM, 1.6:1 SFA:albumin molar ratio) or healthy pregnant (0.9:1 SFA:albumin) women. Trophoblasts were allowed to migrate for 4 hours before assessing migration. SFA exposure at 1.6:1 molar ratio to albumin significantly decreased trophoblast migration when compared to albumin vehicle controls set at 100% (PAL 69.6 ± 3.1%, STE 63.7 ± 2.6%, and MYR 65.4 ± 2.8%, p<0.01), and this decrease in migration was not observed when trophoblasts were exposed to SFA concentrations reported in healthy pregnant women (PAL 92.1 ± 2.4%, STE 111.8 ± 3.2%, and MYR 107.3 ± 3.3%). To investigate whether SFAs stimulated TLRs on Bewo cells, TLR‐2 and TLR‐4 were blocked for 24 hours prior to incubation with SFAs. Blockade of TLR‐4 on Bewo cells significantly restored trophoblast migration capacity when exposed to all SFAs (PAL 108.5 ± 6.3%, STE 108.4 ± 4.3%, and MYR 110.2 ± 3.0%, p<0.01). However, blockade of TLR‐2 only restored migration after exposure to PAL (106.1 ± 3.8%, p<0.01). Additionally, cytotoxicity and reactive oxygen species (ROS) generation assays were performed to determine if decreased trophoblast migration was due to cellular damage mechanisms. Exposure to 0.2 mM MYR significantly enhanced ROS production when compared to control ROS levels (Control MFI: 876.4 ± 102.8, MYR MFI: 1474 ± 129.8, p<0.05), but this increase in ROS generation did not result in enhanced cytotoxicity. PAL or STE exposure did not significantly alter ROS production or cytotoxicity in Bewo trophoblasts. Altogether, our data demonstrates that SFAs attenuate trophoblast migration through TLR signaling mechanisms. Further studies are ongoing to examine TLR‐driven phenotypic alterations in Bewo trophoblasts that result in decreased trophoblast migration. The major findings of this study reveal the impact of elevated SFAs on the pathophysiology of early onset preeclampsia. Support or Funding Information Funding: T32HL105324, P01HL051971, and P20GM104357. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .