Evaluation of Carbon Monoxide as a Therapeutic for Preeclampsia

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McRae, Karalyn
Preeclampsia , Pregnancy , Carbon monoxide
Preeclampsia (PE), a hypertensive complication of pregnancy, is one of the leading causes of maternal and neonatal morbidity and mortality. The etiology of PE is not well-understood, however it is widely accepted to occur in two stages: poor uteroplacental perfusion and placental ischemia, which subsequently leads to a systemic maternal inflammatory response and multi-organ effects. Although cigarette smoking during pregnancy is known to cause aberrant placental development and adverse pregnancy outcomes, smoking reduces the risk of PE by 33% in a dose-dependent manner. The same risk reduction does not hold true for users of smokeless tobacco products. This has lead to the notion that carbon monoxide (CO), one of the byproducts of cigarette combustion, may confer this decrease in PE risk. Endogenously, CO is produced through the degradation of heme by heme oxygenase (HO), and it has been suggested that modulation of the HO/CO system may attenuate the development or progression of PE. The studies presented herein demonstrate that low doses of CO, delivered through gaseous CO or CO donor molecules, may exhibit physiological benefits and have therapeutic potential during complicated pregnancies. Firstly, the challenges associated with reproducing the AdsFlt-1-induced mouse model of PE for studying the effects of CO in complicated pregnancies were investigated. Clinically, inhaled CO was shown to moderately increase biological CO above endogenous levels, and increase vascular responses in the cutaneous microvasculature. In mice, it is demonstrated that the CO-releasing molecule (CORM-A1) is able to transiently increase biological CO levels. CORM-A1 delivered in mid-gestation, resulted in increased CO, without adverse maternal or fetal effects, indicating the potential for CORM-A1 as a novel method to deliver CO during pregnancy. Collectively, the data presented in this thesis verify that low dose CO may have therapeutic properties to improve endothelial dysfunction, increase placental perfusion, and reduce progression of the clinical signs of PE.
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