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175 Inhibiton of Tumour Necrosis Factor Alpha Signalling Improves Vascular Remodelling and Decreases the Pro-Inflammatory and Cytotoxic Phenotype of Peripheral Natural Killer Cells in a Model of Chronic Hypertension in Pregnancy
  1. Heather Small,
  2. Ryszard Nosalski,
  3. Hannah Morgan,
  4. Tomasz Guzik,
  5. Delyth Graham,
  6. Christian Delles
  1. University of Glasgow

Abstract

Objective Pregnancy induces extensive yet relatively rapid remodelling of the cardiovascular (CV) system, however, little is known about this adaptation in women with pre-existing CV disease. We have previously characterised the stroke prone spontaneously hypertensive rat (SHRSP) as a model of deficient uterine artery remodelling and identified an increase in pro-inflammatory TNFÎ ± relative to the normotensive WKY strain during pregnancy.

Design and method SHRSP were treated with etanercept (0.8 mg/kg) or vehicle at gestational day (GD) 0, 6, 12 and 18. Animals were sacrificed at GD18. SHRSP, SHRSP treated with etanercept (ETN) and WKY (n = 6) were used for vascular studies. An independent set of animals (n = 6) were used for flow cytometry analysis.

Results Etanercept significantly reduced systolic blood pressure in the SHRSP after GD 12 (ΔSBP GD 10–21 SHRSP 12.0 ± 4.17 vs. ETN 25.8 ± 4.27 mmHg; p < 0.05). Analysis of GD18 uterine arteries showed that etanercept significantly reduced uterine artery contractile ability (SHRSP 57.3 ± 8.75 vs. ETN 35.2 ± 2.19 kPa; p < 0.01) and increased carbachol response (SHRSP 13.8 ± 3.8% vs. ETN 40.1 ± 3.25%; p < 0.05). Characterisation of uteroplacental blood flow using Doppler showed that etanercept significantly reduced resistance index relative to SHRSP (SHRSP 0.79 ± 0.02 vs. ETN 0.61 ± 0.02 resistance index; p < 0.01). Etanercept significantly increased litter size in the SHRSP (SHRSP 7.80 ± 0.44 vs. ETN 12.75 ± 0.94 fetuses), reduced resorption frequency (SHRSP 66.7% vs. ETN 25.0% dams with resorption) and decreased premature glycogen cell loss from the placenta. Further, we sought to identify the source of excess TNFÎ ± in the SHRSP. Inflammatory natural killer (NK) cells (CD3- CD161+) were significantly increased in the SHRSP relative to the WKY in the placenta (WKY 11.6 ± 2.39 vs. SHRSP 659.8 ± 201.2 cells/mg; p < 0.01). Etanercept reduced the percentage of NK cells which produced TNFÎ ± in the maternal circulation and placenta in the SHRSP. Additionally, etanercept significantly reduced the number of CD161+ NK cells in the placenta of the SHRSP (SHRSP 659.8 ± 201.2 vs. ETN 148.0 ± 12.62 cells/mg; p < 0.01) by inducing a phenotypic switch to a granzyme Blow, CD161low population.

Conclusions Etanercept improves uterine artery function and pregnancy outcome in the SHRSP. We propose that this is through the limitation of both damaging TNFÎ ± release and cytotoxicity from NK cells.

  • Pregnancy
  • Inflammation
  • Vascular Biology

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