Grape Seed Extract Polyphenols Improve Resistance Artery Function in Pregnant eNOS-/- Mice.

Teresa Tropea,Colin P Sibley,Susan L Greenwood,Elizabeth C Cottrell

doi:10.3389/fphys.2020.588000

Abstract

Hypertension during pregnancy is a leading cause of maternal and fetal morbidity and mortality worldwide, increasing the risk of complications including preeclampsia, intracerebral hemorrhage and fetal growth restriction. Increased oxidative stress is known to contribute to poor vascular function; however, trials of antioxidant supplementation have raised concerns about fetal outcomes, including risk of low birthweight. Grape seed extract polyphenols (GSEP) have been suggested to promote cardiovascular protection, at least in part through antioxidant actions. We tested the hypothesis that administration of GSEP during pregnancy would reduce oxidative stress and improve resistance artery function with no detrimental effects on fetal growth, in an established model of maternal hypertension associated with vascular dysfunction, the endothelial NO synthase knockout (eNOS–/–) mouse. Pregnant C57BL/6J (WT) and eNOS–/– mice received either GSEP (200 mg/kg/day) or drinking water, between gestational (GD) day 10.5 and GD18.5. At GD17.5, maternal systolic blood pressure (SBP) was measured; at GD18.5, maternal malondialdehyde (MDA) concentrations, vascular function of aortic, mesenteric, uterine and posterior cerebral arteries was assessed, and fetal outcome evaluated. GSEP reduced maternal SBP (P < 0.01) and plasma MDA concentrations (P < 0.01) in eNOS–/– mice. Whilst there was no effect of GSEP on vascular reactivity of aortas, GSEP improved endothelial-dependent relaxation in mesenteric and uterine arteries of eNOS–/– mice (P < 0.05 and P < 0.001, respectively) and normalized lumen diameters of pressurized posterior cerebral arteries in eNOS–/– mice (P < 0.001). Supplementation with GSEP had no effect in WT mice and did not affect fetal outcomes in either genotype. Our data suggest that GSEP improve resistance artery function, potentially through antioxidant actions, and provide a basis to further investigate these beneficial effects including in the prevention of intracerebral hemorrhage. Maternal supplementation with GSEP may be a safe intervention to improve outcomes in pregnancies associated with hypertension and vascular dysfunction.

Highlights

There were no differences in maternal fluid intake following Grape seed extract polyphenols (GSEP) treatment compared with water controls in either WT or eNOS−/− mice [WT H2O, 9.8 (6.1–25.7); WT GSEP, 8.1 (5.8–21.8); eNOS−/− H2O, 8.6 (6.1–11.4); eNOS−/− GSEP, 9.9 (7.5–11.5); mL/day]
WT mice were significantly heavier than eNOS−/− mice at GD18.5 (P < 0.01, Table 1), but the treatment with GSEP had no effect on maternal body weight (BW) (Table 1)
In agreement with recently published data in the L-NAME mouse model (Zhu et al, 2018), we found that circulating concentrations of MDA were increased in the maternal plasma of eNOS−/− mice compared with WT control groups, and that treatment with GSEP significantly reduced this marker of lipid peroxidation in the hypertensive strain

Summary

Introduction

Pregnancies complicated by chronic hypertension have an increased risk of adverse perinatal outcomes (Gilbert et al, 2007; Chappell et al, 2008), including fetal growth restriction (FGR), preterm delivery, and perinatal death (Jain, 1997; Sibai et al, 1998; Bramham et al, 2014), as well as life-threatening maternal consequences, such as preeclampsia (PE), superimposed PE, eclampsia, cerebral hemorrhage, and maternal death (Sibai, 2002; Bateman et al, 2006; Bellamy et al, 2007; Moodley, 2008). Excessive ROS may cause or exacerbate endothelial dysfunction (Lum and Roebuck, 2001) and predispose to the development of subsequent maternal cardiovascular disorders, including PE (Miranda Guisado et al, 2012; Schoots et al, 2018; Chiarello et al, 2020; San Juan-Reyes et al, 2020)

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