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Intervention against hypertension in the next generation programmed by developmental hypoxia.

Accepted version
Peer-reviewed

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Authors

Brain, Kirsty L 
Allison, Beth J 
Niu, Youguo 
Cross, Christine M 
Itani, Nozomi 

Abstract

Evidence derived from human clinical studies and experimental animal models shows a causal relationship between adverse pregnancy and increased cardiovascular disease in the adult offspring. However, translational studies isolating mechanisms to design intervention are lacking. Sheep and humans share similar precocial developmental milestones in cardiovascular anatomy and physiology. We tested the hypothesis in sheep that maternal treatment with antioxidants protects against fetal growth restriction and programmed hypertension in adulthood in gestation complicated by chronic fetal hypoxia, the most common adverse consequence in human pregnancy. Using bespoke isobaric chambers, chronically catheterized sheep carrying singletons underwent normoxia or hypoxia (10% oxygen [O2]) ± vitamin C treatment (maternal 200 mg.kg-1 IV daily) for the last third of gestation. In one cohort, the maternal arterial blood gas status, the value at which 50% of the maternal hemoglobin is saturated with oxygen (P50), nitric oxide (NO) bioavailability, oxidative stress, and antioxidant capacity were determined. In another, naturally delivered offspring were raised under normoxia until early adulthood (9 months). Lambs were chronically instrumented and cardiovascular function tested in vivo. Following euthanasia, femoral arterial segments were isolated and endothelial function determined by wire myography. Hypoxic pregnancy induced fetal growth restriction and fetal oxidative stress. At adulthood, it programmed hypertension by enhancing vasoconstrictor reactivity and impairing NO-independent endothelial function. Maternal vitamin C in hypoxic pregnancy improved transplacental oxygenation and enhanced fetal antioxidant capacity while increasing NO bioavailability, offsetting constrictor hyper-reactivity and replenishing endothelial function in the adult offspring. These discoveries provide novel insight into mechanisms and interventions against fetal growth restriction and adult-onset programmed hypertension in an animal model of complicated pregnancy in a species of similar temporal developmental milestones to humans.

Description

Keywords

Animals, Antioxidants, Ascorbic Acid, Female, Fetal Growth Retardation, Fetal Hypoxia, Hypertension, Hypoxia, Nitric Oxide, Oxidative Stress, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Sheep

Journal Title

PLoS Biol

Conference Name

Journal ISSN

1544-9173
1545-7885

Volume Title

17

Publisher

Public Library of Science (PLoS)
Sponsorship
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
Isaac Newton Trust (MINUTE 544(I))
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (072256/Z/03/Z)
Biotechnology and Biological Sciences Research Council (BB/E002668/1)
British Heart Foundation (None)
The Royal Society (wm062239)
British Heart Foundation (None)
British Heart Foundation (None)
Wellcome Trust (072256/Z/03/A)
Wellcome Trust (089941/Z/09/A)
Lister Institute of Preventive Medicine (unknown)
Lister Institute of Preventive Medicine (unknown)
British Heart Foundation (RG/17/8/32924)
British Heart Foundation