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

Cells

Cinthya Echem¹  ElianaHiromi Akamine¹  MariaHelena Catelli de Carvalho¹  Tiago Januário Costa¹  Elisabet Vila²  Francesc Jiménez-Altayó²  AnaPaula Dantas³  Rita Tostes⁴ 

[1] Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-900, Brazil;Facultat de Medicina, Departament de Farmacologia, Terapèutica i Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain;Group of Atherosclerosis and Coronary Disease, Institut Clinic del Torax, Institut d’Investigaciones Biomédiques August Pi I Sunyer (IDIBAPS), 08036 Barcelona, Spain;Pharmacology Department, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo 14049-900, Brazil;

关键词: estrogen;    aging;    estrogen receptor variants;    cerebrovascular function;    menopause;    hormone replacement therapy;   

DOI  :  10.3390/cells8101217

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown