Dataset Information

Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ER?36.

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?-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?66) expression and its variants revealed an increased expression of ER?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.

SUBMITTER: Costa TJ

PROVIDER: S-EPMC6829869 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Costa Tiago Januário TJ Jiménez-Altayó Francesc F Echem Cinthya C Akamine Eliana Hiromi EH Tostes Rita R Vila Elisabet E Dantas Ana Paula AP Carvalho Maria Helena Catelli de MHC

Cells 20191008 10

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 w ...[more]

PMID: 31597326

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Project description:ER?36 is a naturally occurring, membrane-associated, isoform of estrogen receptor ?. The expression of ER?36 is due to alternative splicing and different promoter usage. ER?36 is a dominant-negative effector of ER?66-mediated transactivational activities and has the potential to trigger membrane-initiated mitogenic, nongenomic, estrogen signaling; however, the subcellular localization of ER?36 remains controversial. To determine the cellular localization of ER?36 in estrogen-responsive human uterine smooth muscle (ht-UtSMC) and leiomyoma (fibroid; ht-UtLM) cells, we conducted systematic confocal microscopy and subcellular fractionation analysis using ER?36 antibodies. With Image J colocalizaton analysis plugin, confocal images were analyzed to obtain a Pearson's Correlation Coefficient (PCC) to quantify signal colocalization of ER?36 with mitochondrial, endoplasmic reticulum, and cytoskeletal components in both cell lines. When cells were double-stained with an ER?36 antibody and a mitochondrial-specific dye, MitoTracker, the PCC for the two channel signals were both greater than 0.75, indicating strong correlation between ER?36 and mitochondrial signals in the two cell lines. A blocking peptide competition assay confirmed that the mitochondria-associated ER?36 signal detected by confocal analysis was specific for ER?36. In contrast, confocal images double-stained with an ER?36 antibody and endoplasmic reticulum or cytoskeletal markers, had PCCs that were all less than 0.4, indicating no or very weak signal correlation. Fractionation studies showed that ER?36 existed predominantly in membrane fractions, with minimal or undetected amounts in the cytosol, nuclear, chromatin, and cytoskeletal fractions. With isolated mitochondrial preparations, we confirmed that a known mitochondrial protein, prohibitin, was present in mitochondria, and by co-immunoprecipitation analysis that ER?36 was associated with prohibitin in ht-UtLM cells. The distinctive colocalization pattern of ER?36 with mitochondria in ht-UtSMC and ht-UtLM cells, and the association of ER?36 with a mitochondrial-specific protein suggest that ER?36 is localized primarily in mitochondria and may play a pivotal role in non-genomic signaling and mitochondrial functions.

Dataset Information

Late Onset of Estrogen Therapy Impairs Carotid Function of Senescent Females in Association with Altered Prostanoid Balance and Upregulation of the Variant ER?36.

Publications

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

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