Effects of hormonal treatment with estrogen on carotid function of senescent females: influence of epigenetic regulation.

Abstract

The incidence of cerebrovascular diseases increases dramatically with aging, although with more alarming rates in females. In fact, in women over 50 years old, cerebrovascular accident (CVA) is the third cause of death and the leading cause physical and cognitive disability worldwide. Aging in women is fully correlated with the reduction of endogenous levels of estrogen, and studies have suggested that this hormone has vasculoprotective effects. The beneficial actions of estrogen in the peripheral circulation involve direct action on blood vessels, mostly related to control of endothelial function. Several clinical and experimental studies have shown that hormonal therapy with estrogen modulates endothelial function and exerts protective effects on vessels such as the aorta, mesenteric and coronary arterioles, but little is known about its effects on cerebral blood vessels. Nevertheless, multicenter, randomized clinical studies have raised doubts about the beneficial effect of estrogen to postmenopausal women. These studies described that the use of hormone replacement therapy (HRT) presents no apparent advantage for the prevention of heart disease, and also, constitutes to hazard for the development of CVA. One explanation for these negative results can be based on the specificity of the response to estrogen in different vascular beds. Another explanation is based on the disparity of age between the studies. In experimental studies, the cardiovascular effects of estrogen have been determined mainly in ovariectomized young females, while clinical trials were conducted mainly in elderly women, who were on average 10 years past menopause onset. These discrepancies have generated the hypothesis that vascular aging natural and / or long time without estrogens may be impediments for estrogen to exert its vasculoprotective effects. The so called "Timing Hypothesis" proposes a possible window of opportunity that should be respected in order to HRT exert its beneficial effects in the vascular system. Through the Program of International Cooperation CAPES/DGU, during the past year in the laboratory of Dr. Elisabet Vila at Universidad Autonoma de Barcelona I was improving and standardizing techniques to study vascular function in the carotid arteries in order to evaluate the role of aging in the effects induced by estrogen on cerebral circulation of females. It is worth to note that this artery is very important for cerebral blood flow and this territory is one of the most affected by aging in humans, and especially in women under HRT. Our preliminary results demonstrate that estrogen has different effects on carotid reactivity of senescent and non-senescent animals, suggesting that aging is a contributing factor for the lack of estrogen beneficial effects on cerebral circulation. Based on question raised by our preliminary data and the literature, the main objective of this project is to evaluate the effects of estrogen on carotid function and to determine the mechanisms by which aging modulates the effects promoted by estrogen. Treatment with estrogen will be performed at different times after ovariectomy, respecting the "Timing Hypothesis". We will perform studies of vascular reactivity and biochemical and molecular analysis of epigenetic changes associated with aging using the model of premature aging [females with senescence-accelerated ( SAMP8)] and their respective control young [female senescence-resistant (SAMR1)].