Intervention against hypertension in the next generation programmed by developmental hypoxia

Autor: 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.
Přispěvatelé: Giussani, Dino A [0000-0002-1308-1204], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
Zdroj: PLoS Biology, Vol 17, Iss 1, p e2006552 (2019)
PLoS Biology
DOI: 10.17863/cam.35623
Popis: 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.
Author summary Adverse conditions during pregnancy can increase the cardiovascular risk of the adult offspring. However, the mechanisms underlying these effects remain unclear, precluding the identification of candidate therapy. In this interventional study in sheep, a species of similar temporal developmental milestones to humans, we adopt an integrative approach, combining studies in vivo with those at the isolated organ, cellular, and molecular levels to investigate consequences of suboptimal pregnancy on the offspring at two stages of life: in the near-term fetus and in the adult. We show that developmental hypoxia, the most common outcome in human suboptimal pregnancy, slows fetal growth and programs high blood pressure in the sheep adult offspring. Maternal treatment with vitamin C in hypoxic pregnancy restored fetal growth and protected against adult-onset hypertension by improving transplacental oxygen delivery, enhancing fetal antioxidant capacity, and increasing the bioavailability of nitric oxide (NO) in the sheep adult offspring. Our discoveries highlight that when considering strategies to reduce the overall burden of heart disease, a much greater attention to prevention rather than treatment is required. Treatment should start as early as possible during the developmental trajectory, rather than waiting until adulthood when the disease process has become irreversible.
Databáze: OpenAIRE
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