Regulation of Vascular Function by Estrogen: Impact of Aging

  • Author / Creator
    Lekontseva, Olga N
  • 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.

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    Doctor of Philosophy
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