Oxidative stress and developmental programming of cardiovascular disease

• Main Author: Hansell, J. A.
• Published: University of Cambridge 2009
• Subjects: 616.1
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603660

Building on a wealth of human and experimental data, these PhD studies present the hypothesis that oxidative stress underlies the molecular basis via which pregnancy complicated by prenatal hypoxia or prenatal under-nutrition contributes to the developmental programming of cardiovascular disease. An integrative approach was employed at the systems, isolated organ and molecular levels using a combination of fetal and adult rat offspring and chronically cathetised, unanaesthetised fetal sheep preparations. The data show that pregnancy complicated by hypoxia or undernutrition promoted asymmetric intrauterine growth restriction with subsequent postnatal catch-up growth. Maternal treatment with melatonin increased the placental expression of antioxidant enzymes and restored birth weight in undernourished but not in hypoxic pregnancy. Hypoxic but not undernourished pregnancy resulted in thickening of the fetal aortic wall with no alterations to the morphology of the fetal heart. In marked contrast, by adulthood offspring of hypoxic pregnancy showed dilated cardiomyopathy with increased vasoconstrictor reactivity in mesenteric arteries, but no changes in aortic structure. Pregnancy complicated by undernutrition did not affect the heart or the aorta in adult offspring but it did programme an increase in vascoconstrictor reactivity to ET-1 in mesenteric arteries. Maternal treatment with melatonin relieved all of the adverse cardiovascular consequences in adult offspring of hypoxic and undernourished pregnancy. Experiments in ovine pregnancy indicate that the xanthine oxidase pathway contributes to the increased generation of reactive oxygen species in hypoxic pregnancy. Combined, the work offers the potential for therapeutic targets for clinical intervention against a developmental origin of cardiovascular disease in complicated pregnancy.