Cardiovascular Effects of Aerobic Exercise Training in Hypoxic-induced Intrauterine Growth Restriction

• Author / Creator

  Reyes Martinez, Laura M

• Fetal hypoxia is one of the most common consequences of complicated pregnancies worldwide. It has been demonstrated that prenatal hypoxia leads to intrauterine growth restriction (IUGR). Being born growth restricted is associated with a decrease in cardiomyocyte proliferation, an increased susceptibility to cardiac ischemia/reperfusion (I/R) injury and impaired endothelial-dependent vascular function later in life, demonstrating that fetal environment during early development is important for cardiovascular health. Both I/R injury and endothelial dysfunction in hypoxic-induced IUGR offspring have been associated with an increase in the production of reactive oxygen species. Moreover, TNF-related weak inducer of apoptosis (TWEAK) induces cardiomyocyte proliferation through activation of the fibroblast growth factor-inducible molecule 14 (Fn-14) receptor. The TWEAK/Fn-14 pathway has not being studied in hypoxia-induced IUGR offspring. Early interventions are needed to ultimately reduce later life risk for cardiovascular disease. We tested whether aerobic exercise prevents the development of cardiovascular diseases in hypoxic-induced IUGR offspring. In addition, we tested whether the TWEAK/Fn-14 pathway play a role in cardiomyocyte proliferation, and this is associated with an increase susceptibility to cardiac I/R injury. Pregnant Sprague Dawley rats were exposed to control (21% oxygen) or hypoxia (11% oxygen) conditions from gestational day 15 to 21. Male and female offspring from normoxic (control) and hypoxic (IUGR) pregnancies were randomized at 10 weeks of age to either an exercise-trained or sedentary group. After acclimatization, rats ran on a treadmill for 6 weeks; 5 days/week, 30 min/day at 20 m/min. Twenty-four hours after the last bout of exercise, animals were euthanized and concentration response curves to phenylephrine and methylcholine were performed in second order mesenteric and gastrocnemius muscle arteries, in the presence or absence of L-NAME (100 µM), MnTBAP (10 µM), apamin (0.1 µM) and TRAM-34 (10 µM), or indomethacin (5 µM). On the same experimental day, ex vivo cardiac function was determined using a working heart preparation. Hearts were perfused for 10 min in retrograde Langendorff mode, and then switched to working heart mode. Global, normothermic flow ischemia was induced for 10 min. Following ischemia, hearts were reperfused for 40 min. Superoxide production in cardiac tissue was assessed. In a second set of experiments, ventricular cardiomyocytes were isolated at postnatal day one. Proliferation and protein expression of Fn-14 were determined. Cardiomyocyte proliferation was also assessed in the presence or absence of TWEAK. Aerobic exercise training improved endothelium-derived hyperpolarization-mediated vasodilation only in IUGR male offspring. Moreover, aerobic exercise training improved baseline cardiac performance and decreased superoxide generation in male control offspring while in hypoxic-induced IUGR offspring the opposite effect was observed. There was no effect of IUGR or exercise on cardiac or vascular function in female offspring. Being born growth restricted was not associated with differences in the Fn-14 protein expression or cardiomyocyte proliferation. After being in culture for 72-hours, cardiomyocytes from IUGR male offspring had a decreased proliferation compared to controls. Our findings demonstrated that in IUGR populations, a common preventive strategy such as aerobic exercise may represent a secondary stressor to the cardiovascular physiology. The results from the present study also highlight that when examining the mechanisms by which exercise impacts the cardiovascular system in a susceptible population, sexual dimorphism must be considered.

• Subjects / Keywords

  • Cardiovascular function
  • Intrauterine growth restriction
  • Aerobic exercise training

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R34B2XJ8H

• License

  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.