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Intervention against hypertension in the next generation programmed by developmental hypoxia
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 shar...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342530/ https://www.ncbi.nlm.nih.gov/pubmed/30668572 http://dx.doi.org/10.1371/journal.pbio.2006552 |
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author | Brain, Kirsty L. Allison, Beth J. Niu, Youguo Cross, Christine M. Itani, Nozomi Kane, Andrew D. Herrera, Emilio A. Skeffington, Katie L. Botting, Kimberley J. Giussani, Dino A. |
author_facet | Brain, Kirsty L. Allison, Beth J. Niu, Youguo Cross, Christine M. Itani, Nozomi Kane, Andrew D. Herrera, Emilio A. Skeffington, Katie L. Botting, Kimberley J. Giussani, Dino A. |
author_sort | Brain, Kirsty L. |
collection | PubMed |
description | 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 [O(2)]) ± 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 (P(50)), 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. |
format | Online Article Text |
id | pubmed-6342530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-63425302019-02-01 Intervention against hypertension in the next generation programmed by developmental hypoxia Brain, Kirsty L. Allison, Beth J. Niu, Youguo Cross, Christine M. Itani, Nozomi Kane, Andrew D. Herrera, Emilio A. Skeffington, Katie L. Botting, Kimberley J. Giussani, Dino A. PLoS Biol Research Article 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 [O(2)]) ± 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 (P(50)), 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. Public Library of Science 2019-01-22 /pmc/articles/PMC6342530/ /pubmed/30668572 http://dx.doi.org/10.1371/journal.pbio.2006552 Text en © 2019 Brain et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Brain, Kirsty L. Allison, Beth J. Niu, Youguo Cross, Christine M. Itani, Nozomi Kane, Andrew D. Herrera, Emilio A. Skeffington, Katie L. Botting, Kimberley J. Giussani, Dino A. Intervention against hypertension in the next generation programmed by developmental hypoxia |
title | Intervention against hypertension in the next generation programmed by developmental hypoxia |
title_full | Intervention against hypertension in the next generation programmed by developmental hypoxia |
title_fullStr | Intervention against hypertension in the next generation programmed by developmental hypoxia |
title_full_unstemmed | Intervention against hypertension in the next generation programmed by developmental hypoxia |
title_short | Intervention against hypertension in the next generation programmed by developmental hypoxia |
title_sort | intervention against hypertension in the next generation programmed by developmental hypoxia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342530/ https://www.ncbi.nlm.nih.gov/pubmed/30668572 http://dx.doi.org/10.1371/journal.pbio.2006552 |
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