Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ERα36.

Costa Costa,Jiménez-Altayó Jiménez-Altayó,Akamine Akamine,Carvalho Carvalho,Tostes Tostes,Echem Echem,Dantas Dantas,Vila Vila

doi:10.3390/cells8101217

Abstract

Recent analysis of clinical trials on estrogen therapy proposes the existence of a therapeutic window of opportunity for the cardiovascular benefits of estrogens, which depend on women’s age and the onset of therapy initiation. In this study, we aimed to determine how vascular senescence and the onset of estrogen treatment influence the common carotid artery (CCA) function in senescent and non-senescent females. Ovariectomized female senescence-accelerated (SAMP8) or non-senescent (SAMR1) mice were treated with vehicle (OVX) or 17β-estradiol starting at the day of ovariectomy (early-onset, E2E) or 45 days after surgery (late-onset, E2L). In SAMR1, both treatments, E2E and E2L, reduced constriction to phenylephrine (Phe) in CCA [(AUC) OVX: 193.8 ± 15.5; E2E: 128.1 ± 11.6; E2L: 130.2 ± 15.8, p = 0.004] in association with positive regulation of NO/O2- ratio and increased prostacyclin production. In contrast, E2E treatment did not modify vasoconstrictor responses to Phe in OVX-SAMP8 and, yet, E2L increased Phe vasoconstriction [(AUC) OVX: 165.3 ± 10; E2E: 183.3 ± 11.1; E2L: 256.3 ± 30.4, p = 0.005]. Increased vasoconstriction in E2L-SAMP8 was associated with augmented thromboxane A2 and reduced NO production. Analysis of wild-type receptor alpha (ERα66) expression and its variants revealed an increased expression of ERα36 in E2L-SAMP8 in correlation with unfavorable effects of estrogen in those animals. In conclusion, estrogen exerts beneficial effects in non-senescent CCA, regardless of the initiation of the therapy. In senescent CCA, however, estrogen loses its beneficial action even when administered shortly after ovariectomy and may become detrimental when given late after ovariectomy. Aging and onset of estrogen treatment are two critical factors in the mechanism of action of this hormone in CCA.

Highlights

The female aging process and associated disorders may be linked to changes in the hormonal milieu [1]
We describe that the onset of estrogen therapy modifies the vascular function of ovariectomized senescent female mice (SAMP8)
Our findings are consistent with new clinical studies suggesting that the beneficial effects of estrogen therapy in the cardiovascular system depend on the

Summary

Introduction

The female aging process and associated disorders may be linked to changes in the hormonal milieu [1]. Of all aging-related disorders, cardiovascular disease is the leading cause of morbidity and mortality in older women [2]. Estrogen modulates several pathways that are closely associated with aging, it remains unknown whether estrogen can delay cardiovascular senescence, or how estrogen-mediated responses occur in a senile vasculature. In 1985, the observational study Nurses’ Health Study reported that estrogen therapy reduces the risk of cardiovascular disease in postmenopausal women [3]. In agreement with these clinical data, many experimental studies demonstrated that estrogen has beneficial effects in several signaling pathways in the vascular system [4,5,6,7,8,9].

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Methods

Conclusion