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Regional heterogeneity of the vascular dysfunction in db/db mice : role of reactive oxygen species

University of British Columbia

Background: The high mortality and morbidity rates associated with diabetes are mainly attributed to its cardiovascular complications. It remains questionable whether diabetes has a general deleterious effect on the vasculature, or if different arteries exhibit differential vulnerability to the diabetic milieu. This thesis compared the functional adaptation of three arteries: the aorta, carotid and femoral arteries, to the diabetic milieu present in db/db mice, and elucidated the mechanisms underlying the arteries' differential adaptation. Additionally, the functional and molecular alterations in the aorta and femoral artery in response to moderate-intensity exercise training were compared. Methods: Vasodilatory and contractile responses were examined in isolated aortae, carotid and femoral arteries from db/db and control mice to assess the endothelium and vascular smooth muscles' functions. Additionally, the protein expressions of endothelial nitric oxide synthase (eNOS), Akt, cyclooxygenase and superoxide dismutase (SOD) isoforms were examined. In parallel, plasma markers of glycemia, oxidative stress, inflammation, and dyslipidemia were measured. Thereafter, a correlation analysis was performed to estimate the strength of association between plasma variables and vascular responses. Results: The aortae of db/db mice exhibited a progressive impairment in endothelial and vascular smooth muscle functions. The carotid artery was the most resilient and maintained unaltered functional responses in db/db mice, likely because the carotid artery, in contrast to the aorta, relaxes in response to superoxide anion or peroxynitrite. The femoral arteries of db/db mice showed reduced endothelium-dependent hyperpolarizing factor-mediated vasodilatation and attenuated contractile responses, probably due to the lack of expression of extracellular SOD in the femoral artery. The benefits of exercise training were confined to nitric oxide-mediated vasodilatation in the aortae and femoral arteries of db/db mice, and were associated with increased eNOS/Akt and SOD expressions and reduced cardiovascular risk factors. Conclusions: Substantial heterogeneity exists between the aorta, carotid and femoral arteries both at functional (signalling pathways) and molecular levels (protein expression) under physiological and diabetic conditions. Understanding regional differences in vasomotor control, coupled with advanced drug delivery systems will open new venues for developing therapies that target specific vascular beds with minimal systemic side effects.

Text

2012-04-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42182

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/