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 B_low, CD161_low 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.