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Dehydroepiandrosterone Modulates Endothelial Nitric Oxide Synthesis Via Direct Genomic and Nongenomic Mechanisms

Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa 56100, Italy.
Endocrinology (Impact Factor: 4.5). 09/2003; 144(8):3449-55. DOI: 10.1210/en.2003-0044
Source: PubMed

ABSTRACT

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction.

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    • "These latter receptors are possibly localized within membrane rafts and mediate rapid activation of intracellular signaling cascades [28], which in some cases are identical to cascades normally activated by growth factors, such as the Src/PI3K/ Akt or the Src/Ras/Raf/Erk1/2 pathways [15] [29]. While DHEA has been shown to induce similar cascades in neuronal cells [30] [31], little is known about the action of DHEAS, especially on cells of the reproductive system, although it has been shown to be produced in rodent gonads [32] [33]. "

    Full-text · Article · Mar 2014 · Experimental and Clinical Endocrinology & Diabetes
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    • "These latter receptors are possibly localized within membrane rafts and mediate rapid activation of intracellular signaling cascades [28], which in some cases are identical to cascades normally activated by growth factors, such as the Src/PI3K/ Akt or the Src/Ras/Raf/Erk1/2 pathways [15] [29]. While DHEA has been shown to induce similar cascades in neuronal cells [30] [31], little is known about the action of DHEAS, especially on cells of the reproductive system, although it has been shown to be produced in rodent gonads [32] [33]. "
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    ABSTRACT: Dehydroepiandrosterone sulfate (DHEAS) is a circulating steroid produced in the adrenal cortex, brain, and gonads. Whereas a series of investigations attest to neuroprotective effects of the steroid in the brain, surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. Here we demonstrate that DHEAS acting on the spermatogenic cell line GC-2 induces a time- and concentration-dependent phosphorylation of c-Src and Erk1/2 and activates the transcription factors ATF-1 and CREB. These actions are consistent with the non-classical signaling pathway of testosterone and suggest that DHEAS is a pro-androgen that is converted into testosterone in order to exert its biological activity. The fact, however, that steroid sulfatase mRNA was not detected in the GC-2 cells and the clear demonstration of DHEAS-induced activation of Erk1/2, ATF-1 and CREB after silencing the androgen receptor by siRNA clearly contradict this assumption and make it appear unlikely that DHEAS has to be converted in the cytosol into a different steroid in order to activate the kinases and transcription factors mentioned. Instead, it is likely that the DHEAS-induced signaling is mediated through the interaction of the steroid with a membrane-bound G-protein-coupled receptor, since silencing of Gnα11 leads to the abolition of the DHEAS-induced stimulation of Erk1/2, ATF-1, and CREB. The investigation presented here shows a hormone-like activity of DHEAS on a spermatogenic cell line. Since DHEAS is produced in male and female reproductive organs, these findings might help to define new roles for DHEAS in the physiology of reproduction.
    Full-text · Article · Aug 2013 · Biochimica et Biophysica Acta
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    • "In addition, studies, in vitro, found that DHEA can modulate the output of the synthesis of nitric oxide endothelium of blood vessels[34] and angiogenesis.[35] "
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    ABSTRACT: The purpose of this work- was to study the dynamics of biochemical parameters of human saliva and analyze the features of the chemical composition of the saliva of women with abnormal pregnancy and in periodontitis against pregnancy. THE STUDY INCLUDED FOUR GROUPS OF WOMEN: a control group of nonpregnant women of childbearing age (10), pregnant women with physiological pregnancy (24-28 weeks) without any signs of periodontal disease (10), pregnant with a generalized periodontitis I--II degrees in remission (10), women with pathological pregnancy with no signs of periodontal inflammation (10). In each of the groups over two samples of saliva were collected, the first collection of saliva in the morning on an empty stomach. Then mouthwash 0.9% sodium chloride solution was assigned and after 30 minutes the second portion of saliva. By enzyme immunoassay in samples of saliva of control groups of nonpregnant and pregnant women, as well as women with signs of a pathological course of pregnancy, the content of estriol, testosterone, and dehydroepiandrosterone sulfate was determined. Statistical data analysis was performed by the standard technique using Student's t-test. The results of biochemical analysis of saliva samples collected before rinsing the mouth with saline in groups of healthy nonpregnant and pregnant women were compared. It was established that during pregnancy the concentration of salivary estriol increases, but in pregnant women with periodontitis, the amount of this hormone in the saliva was significantly reduced. The highest content of testosterone in saliva samples, observed in healthy pregnant women, was significantly higher than nonpregnant women. In pregnant women with periodontitis concentration of testosterone in saliva is reduced, while remaining significantly higher than its level in the saliva of nonpregnant women. The highest concentration of testosterone is observed in the saliva of healthy pregnant women with periodontitis, but the smallest concentration of testosterone is found in the saliva of nonpregnant women. Also the nonpregnant group has the lowest levels of DHEA in pregnancy, and its content increases almost threefold when periodontal disease further grows. It was established that periodontitis against pregnancy is characterized by higher levels of salivary DHEA sulfate and lower estriol, compared with a control group of pregnant women.
    Full-text · Article · Mar 2012 · Indian Journal of Human Genetics
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