Sex steroid hormones differentially regulate nitric oxide synthase and arginase activities in the proximal and distal rabbit vagina

Traish, Abdul; Kim, Noel N.; Yh, Huang; Min, Kweon Sik; Munárriz, Ricardo; Goldstein, Irwin

doi:10.1038/sj.ijir.3901097

Cited by 40 publications

(35 citation statements)

References 43 publications

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“…For instance, arginase is increased in diabetic blood vessels, and the deficit in NO is normalized by adding an arginase inhibitor (Romero et al, 2008). Because estrogens positively regulate arginase expression and activity in nonvascular tissues (Traish et al, 2003), some of our results on NO production could be interpreted by differences in ER␣-versus ER␤-mediated differences in arginase expression.…”

Section: Discussionmentioning

confidence: 93%

Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes

Cignarella¹,

Bolego²,

Pelosi³

et al. 2008

J Pharmacol Exp Ther

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Estrogen is known to affect vascular function and diabetes development, but the relative contribution of estrogen receptor (ER) isoforms is unclear. The aim of this study was to determine how individual ER isoforms modulate inflammatory enzymes in the vascular wall of control and streptozotocin (STZ)-injected rodents. Primary cultures of rat aortic smooth muscle cells (SMCs) were stimulated with inflammatory agents in the presence or absence of increasing concentrations of the ER␣ and ER␤-selective agonists 4,4Ј,4ЈЈ-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) and diarylpropionitrile (DPN), respectively. The production of inducible nitric-oxide synthase (iNOS), a classical indicator of vascular inflammation, was significantly reduced by PPT in control but not diabetic SMCs, whereas it was further enhanced by DPN treatment in both groups. This distinct action profile was not related to changes in ER transcriptional activity. However, extracellular signal-regulated kinase 1/2 signaling was activated by DPN but not by PPT in cytokine-treated SMCs. In cultured aortic rings from both normoglycemic and STZ-diabetic mice, pharmacological activation of ER␣ attenuated cytokine-driven iNOS induction by 30 to 50%. Vascular iNOS levels were decreased consistently when adding 1 nM 17␤-estradiol to aortic tissues from ER␤-but not ER␣-knockout mice. These findings suggest a possible role for ER␣-selective ligands in reducing vascular inflammatory responses under normo-and hyperglycemic conditions. Recent large-scale clinical trials found a significantly lower incidence of diabetes in postmenopausal women on hormone replacement therapy despite no improvement in vascular outcomes (Kanaya et al., 2003; Margolis et al., 2004). The mechanisms accounting for this outcome, however, are largely unknown, although estrogen is increasingly recognized as an important regulator of glucose homeostasis Le May et al., 2006). Because the endogenous hormone binds to its receptors with identical affinity, the metabolic effects of individual estrogen receptor (ER) isoforms, ER␣ and ER␤, are hard to differentiate and appear to be tissue-and speciesspecific. In accordance, there is little information as to how ER␣ and ER␤ affect the course and timeline of diabetic vascular dysfunction, which ultimately results in macrovascular complications of clinical relevance. We previously demonstrated that anti-inflammatory activity of estrogen is impaired in vascular smooth muscle cells (SMCs) from streptozotocin (STZ)-diabetic rats, which display ER␤ overexpression with respect to normoglycemic controls (Maggi et al., 2003). The biological significance of ER␤ overexpression in vascular cells from diabetic rats is unclear. There have been concerns that ER␤-selective agonists may be diabetogenic , whereas they are effective anti-inflammatory agents in selected in vivo models of inflammation (Harris, 2007).Inducible nitric-oxide synthase (iNOS) is a well established marker of vascular inflammation (Bardell and MacLeod, 2001;Nagareddy et al., 200...

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Section: Discussionmentioning

confidence: 93%

Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes

Cignarella¹,

Bolego²,

Pelosi³

et al. 2008

J Pharmacol Exp Ther

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“…A number of studies have demonstrated that ovarian steroids regulate NO and NOS synthesis in various cells and organs [16,25,26,29,35]. In the rat uterus, estradiol-17 inhibits iNOS and stimulates eNOS gene expression [32].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Localization of Nitric Oxide Synthase (NOS) in Mouse Mammary Gland during Reproductive Cycle

Islam

Matsumoto

Tsuchida

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. Nitric oxide (NO) has been proposed as a mediator of postnatal mammary gland development. We investigated the immunohistochemical localization of three isoforms of nitric oxide synthase (NOS) enzymes, neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS), in the mouse mammary gland during reproductive cycle. The NOS isoforms detected in normal mouse mammary glands were the constitutive forms of NOS (nNOS and eNOS). nNOS was localized to the alveoli, myoepithelia, lactiferous ducts and blood vessel endothelia, while eNOS was localized in the alveoli, lactiferous ducts and blood vessel endothelia. The strongest immunoreactivity for both constitutive NOS isoforms was observed in pregnant mice. The differential staining intensity of NOS enzymes in the mammary gland led us to conclude that nitric oxide in the mouse mammary gland is mainly synthesized by constitutive NOS isoforms, and suggest that NO has functional roles in post-pubertal growth and differentiation of the mammary gland.KEY WORDS: immunohistochemistry, mammary gland, mouse, NOS, reproductive cycle.J. Vet. Med. Sci. 71 (7): [945][946][947][948][949] 2009 Nitric oxide (NO) is an intra-and inter-cellular mediator with diverse physiological and pathophysiological functions in numerous cell types [2,9,20,23]. In vivo, this inorganic free radical gas is generated by the conversion of L-arginine to L-citrulline catalyzed by a family of enzymes known as NO synthase (NOS), which exists in three isoforms. These isoforms were named for the tissues in which they were first identified; neuronal NOS (nNOS, NOS-I), endothelial NOS (eNOS, NOS-III), and the macrophage-inducible form (iNOS, NOS-II). In mammals, constitutive forms of NOS (nNOS and eNOS) are strictly Ca-dependent and generate small amounts of NO, which are responsible for modulating the physiological functions of cells. In contrast, under normal physiological conditions, expression of Ca-independent iNOS is very low, even undetectable, but it can be strongly upregulated as a result of cytokine and/or bacterial endotoxin stimulation [7]. However, the distinction between constitutive and inducible NOS has recently become less clearcut. Indeed, it has been shown that each of the three isoforms can be constitutively expressed in a variety of cells and tissues other than those in which they were initially characterized and cloned [1].NO is known to have a potent influence on the reproductive system and reproduction through numerous physiological processes, such as by altering vascular tone, platelet aggregation, cell growth, or by stimulating angiogenesis, remodeling or apoptosis [5,24,30,33,36]. As the mammary gland is regularly subjected to such processes throughout the reproductive life of mammalian females, NO and NOS have been proposed to play an important role in the growth and proliferation of the mammary gland.NO and NOS activity in the adult rat mammary gland was first reported by Onoda and Inano [22], and a role in the growth and differentiation of the mammary gland was sug...

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“…Because estrogens are known to modulate the expression of nNOS in several target organs, such as the hypothalamus (33) and genital tract (30), we explored the effects of supraestrus levels of E 2 on lower urinary tract function and morphology and urethral nNOS expression, as well as the consequences of acute inhibition of nNOS activity by 7-nitroindazole.…”

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confidence: 99%

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Gamé¹,

Allard²,

Escourrou³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Gamé X, Allard J, Escourrou G, Gourdy P, Tack I, Rischmann P, Arnal J-F, Malavaud B. Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression. Am J Physiol Regul Integr Comp Physiol 294: R851-R857, 2008. First published January 9, 2008 doi:10.1152/ajpregu.00467.2007.-Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17␤-estradiol (E2) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic E2 supplementation (80 g ⅐ kg Ϫ1 ⅐ day Ϫ1 , i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of E2 with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in E2-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that longterm supraestrus E2 levels and acute inhibition of nNOS activity had similar functional effects. Finally, E2 decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of E2 increased urethral tone through inhibition of nNOS expression, whereas physiological levels of E2 had no effect. estrogen; neurourology; urethra UP TO 50% OF WOMEN ARE REPORTED to suffer from urinary incontinence or overactive bladder (22). Lower urinary tract function is intimately interrelated to physiological estradiol (E 2 ) variations, as illustrated by the transitory increase in urethral pressure at the peak of E 2 secretion at midcycle (32), its gradual increase during pregnancy (15), and the prevalence of urinary bothers after menopause (6).In woman, estrogen therapy has been shown to prevent postmenopausal cystitis (8) and urinary atrophy and overactive bladder (6). Moreover, clinical data suggest that estrogens partly improve lower urinary tract functioning by improving local trophicity (13). However, regarding urinary incontinence, estrogens either failed to show any effect on stress urinary incontinence (24) or actually increased (in a large multicentric study) the incidence and severity of all types of urinary incontinence (12).The intricate relationship between urine storage and micturition involves a reciprocal balance in the muscle tone of bladder and urethra, which are under spinal and supraspinal controls. Autonomic regulation of the lower urinary tract physiology is driven by all three components of the autonomic nervous system. Nitric oxide (NO), the key neurotransmitter of the nonadrenergic, noncholinergic nerves ...

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Sex steroid hormones differentially regulate nitric oxide synthase and arginase activities in the proximal and distal rabbit vagina

Cited by 40 publications

References 43 publications

Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes

Distinct Roles of Estrogen Receptor-α and β in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes

Immunohistochemical Localization of Nitric Oxide Synthase (NOS) in Mouse Mammary Gland during Reproductive Cycle

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

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