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.
Highlights
Cardiovascular disease kills 1 in 3 people [1]
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
Adopting an integrative approach at the in vivo, isolated organ, and molecular levels, we show that maternal treatment with vitamin C in ovine hypoxic pregnancy protects against both fetal growth restriction and hypertension in the adult offspring
Summary
Cardiovascular disease kills 1 in 3 people [1]. The annual costs for patient care and lost workforce due to heart disease are over US$130 billion in the United States and Canada [2] and over £30 billion in the United Kingdom [3]. Bariatric surgery to decrease the weight of obese women reduced the risk of obesity, insulin resistance, and raised blood pressure in children born after surgery compared to those born before surgery [10,11,12]. These studies highlight a disproportionate risk of disease in offspring born from the same mother but under different in utero conditions, providing strong evidence in humans that the environment experienced during this critical period of development directly influences longterm cardiovascular health
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