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Developmental Programming of Cardiac and Coronary Artery Dysfunction in Adult Male and Female Offspring Exposed to Prenatal Hypoxia
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- Author / Creator
- Hula, Nataliia
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Cardiovascular disease is a leading cause of global mortality and a major contributor to morbidity worldwide. Early epidemiological studies demonstrated that pregnancy complications can impact the health of the offspring in adult life. Fetal hypoxia is one of the most common complications of pregnancy that leads to changes in fetal cardiovascular structure and function and predisposes the offspring to the development of cardiovascular dysfunction in later life; however, the mechanisms remain to be fully elucidated. This PhD thesis focussed on assessing the effect of prenatal hypoxia on offspring cardiovascular function in adult life with a focus on the endothelin-1 (ET-1) system. Moreover, prenatal hypoxia-induced placental oxidative stress contributes to fetal pathophysiology and subsequently predisposes the offspring to the development of cardiovascular dysfunction. Considering that treatment strategies during pregnancy can be complicated by the potential off-target adverse effects on the fetus, our laboratory has been exploring a placenta-targeted therapeutic strategy based on nanoparticle encapsulation of a mitochondrial-targeted antioxidant (nMitoQ). I also aimed to assess the long-term impact of a placenta-targeted treatment strategy during the hypoxic pregnancy on cardiac susceptibility of adult offspring to cardiac ischemia/reperfusion (I/R) injury in adult life. I hypothesized that the ET-1 system contributes to the development of cardiac and coronary artery dysfunction in adult prenatally-exposed hypoxic offspring. Also, prenatal nMitoQ treatment during a hypoxic pregnancy has a long-term beneficial effect on cardiac capacity to tolerate I/R insult in adult offspring.
To assess the effect of prenatal hypoxia on offspring cardiovascular function, pregnant Sprague–Dawley rats were divided into two groups: normoxic controls (housed at atmospheric oxygen throughout pregnancy: 21% O2) or hypoxic dams (exposed to hypoxia from gestational day (GD) 15–21 by placing them in a hypoxic chamber: 11% O2). The offspring born from those pregnancies were aged to 4- or 9.5 month of age. Cardiac function was assessed using isolated working heart preparation in 4-month-old offspring, while coronary artery function was assessed with wire myography in 4- and ~9.5-month-old offspring. To assess the long-term effect of maternal treatment with nMitoQ on offspring cardiac susceptibility to I/R, pregnant Sprague–Dawley rats were intravenously injected via the tail vein with 100 μL of either saline or nMitoQ (125 μmol/L) on GD 15. Rats injected with nMitoQ or saline were then exposed to either hypoxia (11% O2) from GD 15–21, or were housed at 21% O2 throughout pregnancy. Cardiac function of 4-month-old offspring was assessed using isolated working heart preparation.
Prenatal hypoxia was associated with reduced cardiac levels of ET B receptor (ETB) in female offspring, without changes in males. Infusion of ABT-627 (ETA antagonist) before I/R insult tended to improve post-I/R recovery in prenatal hypoxia females; but surprisingly, ABT-627 prevented post-I/R recovery in the prenatal hypoxia males. In coronary arteries, at 4 months of age, constrictor responses to exogenous ET-1 were similar between groups. However, ET-1 levels were increased, and ETB inhibition (with BQ788) tended to decrease ET-1-mediated responses in only prenatal hypoxic females. At 9.5 months of age, ET-1-mediated responses were decreased in only prenatal hypoxic females; with no effect with BQ788. Notably, prenatal hypoxia impaired endothelium-dependent vasodilation in both male and female offspring at 4- and 9.5-months of age that was attributed to an increased prostaglandin H synthase (PGHS)-dependent vasoconstriction.
Maternal nMitoQ treatment improved cardiac tolerance to an I/R insult in both male and female adult offspring born from pregnancies complicated with prenatal hypoxia; however, the calcium regulating mechanisms were sex-specific. In prenatally hypoxia male offspring, maternal nMitoQ treatment increased phospholamban (PLN) levels, tended to decrease phosphorylation of Ca2+/calmodulin kinase δ and increased levels of protein phosphatase 2Ce. In female offspring born from hypoxic pregnancies, maternal nMitoQ resulted in increased phosphorylation of PLN and protein kinase Cε.
My studies suggests that prenatal hypoxia impacted the ET-1 pathway with sex specific differences in cardiac and coronary artery function. I also demonstrated that prenatal hypoxia impaired endothelial-dependent vasodilation in coronary arteries via a PGHS-dependent pathway. Maternal treatment strategies targeted against placental oxidative stress can improve offspring cardiac capacity to tolerate I/R insult by impacting the intracellular mechanisms of calcium cycling. Overall, these data show that understanding the impact of prenatal environment is necessary for precise treatment approaches throughout the lifecourse. -
- Graduation date
- Spring 2023
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- 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.