Enhanced Nitrite-Mediated Relaxation of Placental Blood Vessels Exposed to Hypoxia Is Preserved in Pregnancies Complicated by Fetal Growth Restriction.

Teresa Tropea,Carina Nihlen,Eddie Weitzberg,Mark Wareing,Colin P Sibley,Elizabeth C Cottrell,Jon O Lundberg,Susan L Greenwood

doi:10.3390/ijms22094500

Abstract

Nitric oxide (NO) is essential in the control of fetoplacental vascular tone, maintaining a high flow−low resistance circulation that favors oxygen and nutrient delivery to the fetus. Reduced fetoplacental blood flow is associated with pregnancy complications and is one of the major causes of fetal growth restriction (FGR). The reduction of dietary nitrate to nitrite and subsequently NO may provide an alternative source of NO in vivo. We have previously shown that nitrite induces vasorelaxation in placental blood vessels from normal pregnancies, and that this effect is enhanced under conditions of hypoxia. Herein, we aimed to determine whether nitrite could also act as a vasodilator in FGR. Using wire myography, vasorelaxant effects of nitrite were assessed on pre-constricted chorionic plate arteries (CPAs) and veins (CPVs) from normal and FGR pregnancies under normoxic and hypoxic conditions. Responses to the NO donor, sodium nitroprusside (SNP), were assessed in parallel. Nitrate and nitrite concentrations were measured in fetal plasma. Hypoxia significantly enhanced vasorelaxation to nitrite in FGR CPAs (p < 0.001), and in both normal (p < 0.001) and FGR (p < 0.01) CPVs. Vasorelaxation to SNP was also potentiated by hypoxia in both normal (p < 0.0001) and FGR (p < 0.01) CPVs. However, compared to vessels from normal pregnancies, CPVs from FGR pregnancies showed significantly lower reactivity to SNP (p < 0.01). Fetal plasma concentrations of nitrate and nitrite were not different between normal and FGR pregnancies. Together, these data show that nitrite-mediated vasorelaxation is preserved in FGR, suggesting that interventions targeting this pathway have the potential to improve fetoplacental blood flow in FGR pregnancies.

Highlights

Fetal growth restriction (FGR) is the failure of a fetus to achieve its biological growth potential in utero and affects up to 5–10% of pregnancies [1]
The results of this study demonstrate that there is similar nitrite-dependent vasorelaxation in human chorionic plate vessels from pregnancies complicated by FGR as compared with vessels from normal pregnancies
The present findings confirm and extend our previous observations in normal pregnancy [16] showing vasorelaxant responses to nitrite to be higher in chorionic plate arteries (CPAs) than CPVs; this same pattern is observed in FGR

Summary

Introduction

Fetal growth restriction (FGR) is the failure of a fetus to achieve its biological growth potential in utero and affects up to 5–10% of pregnancies [1]. This pregnancy complication is a clinically important problem, both perinatally and into adult life. FGR is associated with an increased risk of metabolic syndrome [4], cardiovascular pathologies [5] and impaired neurological and cognitive development [6] in adult life. In pregnancies complicated by placental insufficiency, uteroplacental vascular resistance is high and Doppler flow-velocity waveforms show a high pulsatility index and absent or reversed diastolic blood flow in the umbilical circulation, which indicate impaired placental perfusion and correlate with FGR [8]

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