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Regulation of Vascular Function by Estrogen: Impact of Aging Open Access


Other title
cardiovascular disease
aging vascular system
hormone replacement therapy
Type of item
Degree grantor
University of Alberta
Author or creator
Lekontseva, Olga N
Supervisor and department
Davidge, Sandra (Obstetrics/Gynecology and Physiology)
Examining committee member and department
Benishin, Christina (Physiology)
Fernandez-Patron, Carlos (Biochemistry)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
Ovarian endocrine function has a major impact on homeostatic mechanisms in the cardiovascular system in women. In particular, estrogens play an important role in the regulation of vascular function. Epidemiological and experimental evidence links increased risk for cardiovascular disease with estrogen deficient states of various etiologies. It has however become recognized that vascular effects of exogenous estrogens are complex, and may result in a range of effects, from beneficial to contrabeneficial, depending on the vascular conditions. Although the mechanisms are not fully explained, vasoprotective potential of estrogen is attenuated in the presence of vascular risk factors, including aging (e.g., postmenopausal age). Aging is associated with pro-inflammatory and pro-oxidant alterations in the vascular microenvironment, along with an imbalance of local vasoactive mechanisms. The results of this thesis reinforce evidence of augmented endothelin (ET) mediated vasoconstriction together with deficient nitric oxide (NO) modulation of resistance artery function in an animal model of female aging (i.e. aging ovariectomized rat). We examined the hypothesis that dysfunction of the enzymes, matrix metalloproteinase (MMP) and neuronal nitric oxide synthase (nNOS), which are sources of ET and NO in the vasculature, contributes to the pro-hypertensive postmenopausal phenotype. We found that MMP played a significant role in vasoconstriction through generation of ET in aging, but not young females. On the other hand, in aging, there was a loss of nNOS-mediated vascular relaxation, where this enzyme further contributed to oxidative stress as a source of superoxide. Vasoprotective potential of estrogen was evaluated in both young and aging conditions, i.e. rats receiving estrogen replacement following ovariectomy. Our experimental findings indicate that estrogen signaling is impaired in aging, partially as a consequence of dysfunction at the level of its mediators, MMP and nNOS. Indeed, estrogen treatment further increased the acute role of MMP in vasoconstriction and did not restore nNOS-mediated vasorelaxation. These studies illustrate the concept that fundamental vasoprotective pathways regulated by estrogen under controlled physiological conditions may turn dysfunctional in aging or other pro-inflammatory, pro-oxidant vascular states. Pharmacological interventions aimed selectively at these altered molecular pathways may yield more effective, non-hormonal therapeutic approaches in cardiovascular medicine.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
1) Chakrabarti S*, Lekontseva O*, Davidge ST. Estrogen is a modulator of vascular inflammation. IUBMB Life. 2008 Jun;60(6):376-82. Review, *equal contribution.2) Lekontseva O, Jiang Y, Davidge ST. Estrogen replacement increases matrix metalloproteinase contribution to vasoconstriction in a rat model of menopause. J Hypertens. 2009 Aug;27(8):1602-8.3) Lekontseva O*, Chakrabarti S*, Davidge ST. Endothelin in the female vasculature: a role in aging? Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R509-16. Review, *equal contribution.4) Lekontseva ON, Rueda-Clausen CF, Morton JS, Davidge ST. Ovariectomy in aged versus young rats augments matrix metalloproteinase-mediated vasoconstriction in mesenteric arteries. Menopause. 2010 May-Jun;17(3):516-23.5) Lekontseva O, Chakrabarti S, Jiang Y, Cheung CC, Davidge ST. Role of neuronal nitric oxide synthase in estrogen-induced relaxation in rat resistance arteries. J Pharmacol Exp Ther. 2011 Nov;339(2):367-75.

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