Long-term cardiovascular and metabolic effects of hypoxia-induced intrauterine growth restriction

  • Author / Creator
    Rueda-Clausen, Christian Federico
  • Cardiovascular and metabolic diseases are still the primary cause of death and disability in modern society. Although genetic factors play a fundamental role in the development of these chronic conditions, the remarkable variability in an individual’s susceptibility to develop these pathologies cannot be completely explained by genetics. The early programming of adult diseases theory became established in the 1980’s, and is now supported by a growing body of evidence demonstrating that exposure to suboptimal environmental conditions during crucial periods of time can predispose an individual to the development of chronic conditions (including cardiovascular and metabolic diseases) later in life. Among the multitude of factors that can cause early programming, we have focused on the study of pregnancy complications leading to fetal hypoxia and causing intrauterine growth restriction (IUGR). To this end, we have used an animal model in which pregnant Sprague Dawley rats were exposed to either normal (∼21% O2) or hypoxic (∼11.5% O2) conditions during the last third of pregnancy. We then followed and studied the cardiovascular and metabolic characteristics of the offspring later in life. The studies presented in this thesis demonstrate that hypoxic prenatal insults have long-term consequences on cardiac structure, function and susceptibility to ischemia. We also demonstrated that programmed susceptibility to myocardial ischemia was associated with changes in cardiac energy metabolism and increased levels of myocardial oxidative stress. Moreover, we described the interaction between prenatal hypoxic insults, aging and sex differences in the later development of cardiovascular conditions. Additional studies presented in this thesis demonstrate that offspring born IUGR are more susceptible to develop most components of the metabolic syndrome when exposed to a high-fat (HF) diet. Furthermore, we also demonstrated that the exacerbated deleterious response to a HF diet described in offspring born IUGR can be prevented by postnatal administration of Resveratrol, which is a natural compound with anti-oxidant and anti-aging properties. In conclusion, the results presented in this thesis are an important contribution to the understanding of the long-term cardiovascular and metabolic effects of prenatal hypoxic insults causing IUGR and provide evidence regarding possible mechanisms and treatment alternatives that could be considered.

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  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Lopaschuk, Gary D. (Pharmacology)
    • Kassiri, Zamaneh (Physiology)
    • Seubert, John M. (Pharmacy and Pharmaceutical Sciences)
    • Giussani, Dino A. (Physiology, Development & Neuroscience (PDN) University of Cambridge)