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

Grant number: 13/19423-9
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2014
Effective date (End): September 30, 2017
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Maria Helena Catelli de Carvalho
Grantee:Tiago Januário da Costa
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):15/26690-9 - Analysis of transcriptional and post-transciptional regulation of estrogen receptor (ER) on altered estrogen-mediated effects in the carotid of aging female mice, BE.EP.DR


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)].

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
COSTA, TIAGO JANUARIO; JIMENEZ-ALTAYO, FRANCESC; ECHEM, CINTHYA; AKAMINE, ELIANA HIROMI; TOSTES, RITA; VILA, ELISABET; DANTAS, ANA PAULA; CATELLI DE CARVALHO, MARIA HELENA. Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ER alpha 36. CELLS, v. 8, n. 10, . (14/03758-4, 13/19423-9, 15/26690-9)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
COSTA, Tiago Januário da. Influence of early and late estrogen treatments in ovariectomized senescence accelerated (SAMP8) and resistant (SAMR1) female mice: a study of the mechanism of action in the carotid.. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

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