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

Author(s)

Costa, Tiago Januario ^{[1, 2, 3, 4]} ; Jimenez-Altayo, Francesc ^[3] ; Echem, Cinthya ^[1] ; Akamine, Eliana Hiromi ^[1] ; Tostes, Rita ^[4] ; Vila, Elisabet ^[3] ; Dantas, Ana Paula ^[2] ; Catelli de Carvalho, Maria Helena ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, BR-05508900 Sao Paulo, SP - Brazil

^[2] Inst Clin Torax, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Grp Atherosclerosis & Coronary Dis, Barcelona 08036 - Spain

^[3] Univ Autonoma Barcelona, Fac Med, Inst Neurociencies, Dept Farmacol Terapeut & Toxicol, Bellaterra 08193 - Spain

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Pharmacol Dept, BR-14049900 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: CELLS; v. 8, n. 10 OCT 2019.
• Web of Science Citations: 0

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 17 beta-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 (ER alpha 66) expression and its variants revealed an increased expression of ER alpha 36 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. (AU)

• FAPESP's process: 14/03758-4 - Study of vascular, metabolic function and epigenetic alterations in senescent females: estrogen influence
• Grantee: Maria Helena Catelli de Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/19423-9 - Effects of hormonal treatment with estrogen on carotid function of senescent females: influence of epigenetic regulation.
• Grantee: Tiago Januário da Costa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 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
• Grantee: Tiago Januário da Costa
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate