UBC Theses and Dissertations
Vascular outcomes and developmental programming in a mouse model of sleep apnea Mohammad, Badran
Obstructive sleep apnea (OSA) is a chronic condition characterized by recurring upper airway collapse during sleep, leading to chronic intermittent hypoxia (CIH) that can evoke oxidative stress and inflammation leading to cardiovascular disease (CVD). Current treatments for OSA are relatively ineffective in preventing CVD. Moreover, the effects of gestational OSA on the health of the offspring are unknown. We hypothesized that 1) antioxidant treatment can improve vascular outcomes in mice exposed to CIH and that 2) gestational intermittent hypoxia (GIH) can adversely impact fetoplacental outcomes and lead to cardiometabolic disease in the adult offspring. The first chapter of this thesis examines the effects of CIH on vascular function, oxidative stress and inflammatory markers in CB57BL/6 male mice with or without treatment with the dietary antioxidant, alpha lipoic acid (ALA). CIH impaired aortic relaxation and basal nitric oxide (NO) production. Furthermore, CIH increased systemic oxidative stress, inflammation and proinflammatory gene expression in the aorta. Treatment with ALA improved endothelial function and reduced oxidative stress and inflammation. In the second chapter, the impact of 14.5 days of GIH on vascular function of pregnant mice is reported. The following were evaluated: uterine artery function, plasma oxidative stress and inflammatory markers, spiral artery remodeling, placental morphology, hypoxia, oxidative stress, and fetal weights. GIH increased placental weights and decreased fetal weights, impaired uterine artery function, increased systemic oxidative stress and inflammation, increased placental hypoxia, and oxidative stress with no effect on spiral artery remodeling. In the third chapter, aortic endothelial and perivascular adipose tissue (PVAT) function were evaluated in sixteen-week-old offspring of dams exposed to GIH only in utero. GIH male offspring had increased body weights and developed metabolic syndrome. Furthermore, aortic relaxation was impaired in offspring with a loss of PVAT anti-contractile effects, which was facilitated by adiponectin. Levels of adiponectin were lower in the PVAT and in plasma. Pyrosequencing of adiponectin promoter in PVAT indicated increased DNA methylation in male GIH offspring. These data suggest that treatment of OSA patients with ALA could be a strategy to improve cardiovascular outcomes. Furthermore, maternal OSA may lead to adverse metabolic and vascular outcomes during adulthood.
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