Redox modulation of the fetal cardiovascular defence to hypoxaemia

Abstract

Episodes of hypoxia in utero present a potentially serious challenge to the fetus, but are counteracted by defence responses including marked redistribution of blood flow from peripheral circulations to the brain. Here, we report the novel observation that the oxidant tone is an important modulator of this cardiovascular defence. Using pregnant Welsh Mountain sheep surgically prepared for long-term recording, we investigated in vivo the effects on the fetal cardiovascular defence to acute hypoxaemia of fetal treatment with the antioxidant vitamin C. The mechanisms via which vitamin C may affect the vascular oxidant tone were investigated by monitoring fetal plasma concentrations of nitrates and nitrites, by determining changes in the activity of superoxide dismutase (SOD) in fetal plasma, and by investigating the effect of vitamin C treatment on the fetal cardiovascular defence to hypoxaemia following nitric oxide (NO) synthase blockade. Fetal treatment with vitamin C markedly depressed the normal femoral constrictor response to acute hypoxaemia in the fetus (5.2 ± 1.0 vs. 1.1 ± 0.3 mmHg (ml min −1 ) −1 , mean ± s.e.m.; P < 0.05) an effect which was completely restored following NO synthase blockade (6.2 ± 1.3 mmHg (ml min −1 ) −1 ). Compared to saline infusion, fetal treatment with vitamin C during acute hypoxaemia also significantly increased fetal plasma SOD activity from normoxic baseline (−8.9 ± 6.5 vs. 15.0 ± 6.6% inhibition, P < 0.05) and decreased the plasma concentration ratio of nitrate:nitrite from normoxic baseline ( NO 3 − :NO 2 − ; 0.15 ± 0.30 vs. −0.29 ± 0.11, P < 0.05). The data provide in vivo evidence of redox modulation of redistribution of blood flow in the fetus, part of the fetal brain sparing during acute hypoxaemic stress.

Developmental Programming of Cardiovascular Dysfunction by Prenatal Hypoxia and Oxidative Stress

“…Therefore, the capacity of vitamin C to scavenge • O 2 − and its ability to prevent the interaction between NO and • O 2 − appear to occur at very different concentrations in vivo . The dose of vitamin C used in the present study was derived from a previous study in our laboratory which achieved elevations in circulating ascorbate concentrations, enabling it to act as an antioxidant in vivo in ovine pregnancy [35], thereby justifying the antioxidant dosing regimen. In rat pregnancy, this equated to ca .…”

The impact of early nutrition on the ageing trajectory

“…As observed in the model of protein restriction and placental insufficiency, evidence of oxidative stress has been demonstrated in this model. This has been reported in the placenta (increased levels of 4-hydroxynonenal and heat-shock protein 70) (103) , and in the heart (increased nitrotyrosine staining and heat-shock protein 70) (102) of rats and in sheep (104) . Furthermore, the administration of the antioxidants allopurinol (104) and vitamin C (105) reversed these phenotypes in sheep.…”

“…This has been reported in the placenta (increased levels of 4-hydroxynonenal and heat-shock protein 70) (103) , and in the heart (increased nitrotyrosine staining and heat-shock protein 70) (102) of rats and in sheep (104) . Furthermore, the administration of the antioxidants allopurinol (104) and vitamin C (105) reversed these phenotypes in sheep. Therefore, it is plausible that hypoxia accelerates ageing in the placenta and cardiovascular systems, potentially leading to eventual cellular senescence, apoptosis and organ dysfunction.…”

Vitamin C Prevents Intrauterine Programming of in vivo Cardiovascular Dysfunction in the Rat

“…The dose of vitamin C used in the present study was derived from a previous study in our laboratory that achieved elevations in circulating ascorbate concentrations within the required 10 mmol/L range in ovine pregnancy. 60 In rat pregnancy, this equated to ca. 1 g kg -1 d -1 of vitamin C administration.…”