Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

Haas, Elvira; Meyer, Matthias R.; Schurr, Ulrich; Bhattacharya, Indranil; Minotti, Roberta; Nguyen, Hung Huy; Heigl, Andres; Lachat, Mario; Genoni, Michele; Barton, Matthias

doi:10.1161/hypertensionaha.107.089995

Cited by 156 publications

(147 citation statements)

References 51 publications

(57 reference statements)

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“…35 Role of the novel ER G protein coupled receptor 30 (GPR30) in the cardiovascular system In addition to the two classical ER subtypes, ERa and ERb, a third membrane-bound and G-protein-coupled ER, GPR30, has been identified in human vascular endothelial cells (ECs) and smooth muscle cells. [36][37][38] Haas et al 37 reported that G-1, a selective stimulator of GPR30, acutely blocked vasoconstrictor-induced changes in intracellular calcium concentrations and vascular tone, resulting in lowering of blood pressure in normotensive rats. Similar vasodilator effects of GPR30 have been confirmed in other studies.…”

Section: Action Of Estrogen On the Cardiovascular Systemmentioning

confidence: 99%

Hormonal effects on blood vessels

Akishita

2012

Hypertens Res

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The incidence of cardiovascular disease (CVD) is lower in younger women than in men of the same age, but it increases after menopause, implicating the atheroprotective action of endogenous estrogen. Although observational studies have suggested the efficacy of estrogen therapy in postmenopausal women, placebo-controlled, randomized trials, such as the Women's Health Initiative, have not confirmed effects of estrogen therapy on CVD. Conversely, basic, experimental research has progressed and provided mechanistic insight into estrogen's action on blood vessels. By contrast, the vascular effects of androgens remain poorly understood and have been controversial for a long time. In recent years, an increasing body of evidence has suggested that androgens may exert protective effects against the development of atherosclerosis, at least in elderly men. Epidemiological studies have shown that the incidence of and mortality due to CVD were increased in elderly men with low testosterone levels, although the efficacy of androgen therapy remains unknown. Furthermore, recent experimental studies have demonstrated the direct action of androgens on the vasculature. In this review, we illustrate the effects of sex steroids on the cardiovascular system, focusing on the action of testosterone on the blood vessels.

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Section: Action Of Estrogen On the Cardiovascular Systemmentioning

confidence: 99%

Hormonal effects on blood vessels

Akishita

2012

Hypertens Res

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“…From biodistribution studies, uptake of the radiotracer in the tumor was receptormediated based on the significantly lower uptake on coinjection with excess17b-estradiol. Care must be taken while performing receptor blocking experiments with high doses of 17b-estradiol as estrogen alters vascular physiology, blood flow and receptor expression levels (39). Consequently, when the blocking dose was injected 1 h before the injection of the radiotracer, we observed higher uptake in organs such as liver and lungs.…”

Section: Discussionmentioning

confidence: 82%

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate^99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

Nayak

Hathaway²,

Ramesh³

et al. 2008

J Nucl Med

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Breast and endometrial cancers are the most common invasive malignancies in women, with more than 217,000 new diagnoses per year in the United States. These cancers are often classified into 2 subtypes based on the expression of the classical estrogen receptor. In this study, we describe a new structural class of neutral tridentate 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivatives for potential use in breast and endometrial cancer imaging. Methods: The 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative was synthesized via the Sonogashira cross-coupling reaction and radiolabeled via the tricarbonyl approach. Radiochemical purity was assessed by high-performance liquid chromatography. Cell-binding studies were performed with human breast adenocarcinoma MCF-7 cells. The in vivo biodistribution of the 99m Tc(I) derivative was evaluated in virgin female C57BL/6 mice in defined phases of the estrous cycle. Biodistribution and SPECT/CT studies were performed with mice bearing MCF-7 and primary human endometrial tumors. Results: Radiochemical analysis demonstrated that the postpurification purity of the 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative was $95%, with a specific activity of 99m Tc of 47.5 TBq/mmol. Cell-binding studies yielded a dissociation constant (mean 6 SEM) of 11 6 1.5 nM. In vivo studies revealed that receptor-mediated uptake was present in all phases of the estrous cycle in reproductive organs and mammary glands but was highest during the diestrous phase of the estrous cycle. Despite high nonspecific uptake in the liver, significant receptor-mediated uptake was observed in target tissues and estrogen receptor-expressing tumors (0.67% for MCF-7 tumors and 0.77% for endometrial tumors). Tumor uptake was reduced by approximately 50% on coinjection with 17b-estradiol. Conclusion: We have characterized a novel neutral tridentate 99m Tc(I)-estradiol-pyridin-2-yl hydrazine derivative for potential use in breast and endometrial cancer imaging. This study represents the first step on a path toward the design of estrogen-based Tc-labeled tracers with improved targeting and SPECT imaging characteristics. Over 250,000 new cases of breast, ovarian, and endometrial cancers were diagnosed in the United States in 2006 (1). Such cancers are often hormonally regulated and can be divided into 2 subtypes on the basis of whether or not tumor cells express the classical estrogen receptor (ER), ERa. Estrogen promotes cell proliferation and inhibits apoptosis through a complex signaling cascade resulting in transcriptional changes that may include the modulation of tumor suppressor function. The presence of ERa in approximately two thirds of breast cancers correlates with whether the tumors are estrogen dependent or independent (2) and represents one of the best prognostic factors in breast cancer because of the availability of antiestrogens such as tamoxifen and fulvestrant and, more recently, the aromatase inhibitors. With the recent characterization of a novel transmembrane ER, GPR30, in multiple cancer t...

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“…GPR30, has been detected in many tissues, including the uterus [22]. GPR30 expression was discovered in the vascular smooth muscle cells of patients with atherosclerosis [23]. Subsequently, it was found that GPR30 expression mediated the proliferation of ovarian [24], endometrial [10], breast [13], and sperm cell [25] tumors.…”

Section: Discussionmentioning

confidence: 99%

G-protein-coupled estrogen receptor-30 gene polymorphisms are associated with uterine leiomyoma risk

Kasap

Turhan

Edgünlü

et al. 2015

Bosn J of Basic Med Sci

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The G-protein-coupled estrogen receptor , GPER-1) is a member of the G-protein-coupled receptor 1 family and is expressed significantly in uterine leiomyomas. To understand the relationship between GPR30 single nucleotide polymorphisms and the risk of leiomyoma, we measured the follicle-stimulating hormone (FSH) and estradiol (E2) levels of 78 perimenopausal healthy women and 111 perimenopausal women with leiomyomas. The participants' leiomyoma number and volume were recorded. DNA was extracted from whole blood with a GeneJET Genomic DNA Purification Kit. An amplification-refractory mutation system polymerase chain reaction approach was used for genotyping of the GPR30 gene (rs3808350, rs3808351, and rs11544331). The differences in genotype and allele frequencies between the leiomyoma and control groups were calculated using the chi-square (χ2) and Fischer' s exact test. The median FSH level was higher in controls (63 vs. 10 IU/L, p=0.000), whereas the median E2 level was higher in the leiomyoma group (84 vs. 9.1 pg/mL, p=0.000). The G allele of rs3808351 and the GG genotype of both the rs3808350 and rs3808351 polymorphisms and the GGC haplotype increased the risk of developing leiomyoma. There was no significant difference in genotype frequencies or leiomyoma volume. However, the GG genotype of the GPR30 rs3808351 polymorphism and G allele of the GPR30 rs3808351 polymorphism were associated with the risk of having a single leiomyoma. Our results suggest that the presence of the GG genotype of the GPR30 rs3808351 polymorphism and the G allele of the GPR30 rs3808351 polymorphism affect the characteristics and development of leiomyomas in the Turkish population.

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Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

Cited by 156 publications

References 51 publications

Hormonal effects on blood vessels

Hormonal effects on blood vessels

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate^99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

G-protein-coupled estrogen receptor-30 gene polymorphisms are associated with uterine leiomyoma risk

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Differential Effects of 17β-Estradiol on Function and Expression of Estrogen Receptor α, Estrogen Receptor β, and GPR30 in Arteries and Veins of Patients With Atherosclerosis

Cited by 156 publications

References 51 publications

Hormonal effects on blood vessels

Hormonal effects on blood vessels

Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers

G-protein-coupled estrogen receptor-30 gene polymorphisms are associated with uterine leiomyoma risk

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Preclinical Development of a Neutral, Estrogen Receptor–Targeted, Tridentate^99mTc(I)-Estradiol-Pyridin-2-yl Hydrazine Derivative for Imaging of Breast and Endometrial Cancers