Constitutive Coexpression of Nitric Oxide Synthase-1 and Soluble Guanylyl Cyclase in Myoepithelial Cells of Mammary Glands in Mice

Wöckel, Achim; Baum, Oliver; Planitzer, Gerit; Rothen‐Rutishauser, Barbara; Gossrau, Reinhart; Abou-Dakn, Michael

doi:10.1159/000088246

Cited by 5 publications

(11 citation statements)

References 33 publications

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“…The lactating mammary gland shows weak nNOS and eNOS immunoreactivity. This agrees with previous studies on the lactating mammary gland, where NOS is involved in the counter current contraction of the myoepithelial cell against oxytocin contraction [31] and regulates mammary vascular tone and blood flow [10,14]. Weak immunolabelling of mammary epithelial cells in the lactation stage also supports the previously proposed hypothesis that NO is produced at low rates in the mammary gland by constitutive NOS [34].…”

Section: Discussionsupporting

confidence: 92%

“…Several studies have been performed to determine the localization and expression patterns of NOS isoforms in the human, rat and mouse mammary gland by immunohistochemistry [10,22,27,31,34]. In humans, Thomsen et al [27] described nNOS immunoreactivity in the myoepithelial cell surrounding the alveoli of the neoplastic mammary gland.…”

Section: Discussionmentioning

confidence: 99%

“…In the adult rat mammary gland, Onoda and Inano [22] reported that eNOS was localized in the myoepithelial cells and nNOS was localized in the alveoli, while iNOS was induced after stimulation with lipopolysaccharide. In mice, Wöckel et al [31] reported that immunohistochemical expression of nNOS was restricted to myoepithelium, and that of eNOS was absent in lactating and non-lactating mouse mammary glands. On the other hand, we found nNOS localization in the alveoli and duct epithelia, as well as myoepithelia, while eNOS localization was seen in the alveoli and duct.…”

Section: Discussionmentioning

confidence: 99%

“…However, other studies in the lactating mammary gland have shown that NO is involved in lactation via effects on milk secretion [10,14,31]. In virgin mice, Bolander [3] showed that NO acts as a second messenger of prolactin by redistributing prolactin receptors from the internal pool to the epithelial cell surface, and is then involved in prolactin-mediated mammary growth.…”

mentioning

confidence: 99%

“…These findings suggest that NO plays important roles in the growth and development of mammary gland. Although NO and NOS activities have been described in the human [27], rat [10,22,34] and mouse [31] mammary gland, there have been no systematic studies on the three isoforms of NOS in the mouse mammary gland in relation to its roles in the different stages of the reproductive cycle. The present study was undertaken in order to investigate the immunohistochemical localization of the three isoforms in the mouse mammary gland in the virgin, pregnant, lactating and weaning states.…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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Reduced Basal Nitric Oxide Production Induces Precancerous Mammary Lesions via ERBB2 and TGFβ

Ren

Zheng

Bommarito

et al. 2019

Sci Rep

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One third of newly diagnosed breast cancers in the US are early-stage lesions. The etiological understanding and treatment of these lesions have become major clinical challenges. Because breast cancer risk factors are often linked to aberrant nitric oxide (NO) production, we hypothesized that abnormal NO levels might contribute to the formation of early-stage breast lesions. We recently reported that the basal level of NO in the normal breast epithelia plays crucial roles in tissue homeostasis, whereas its reduction contributes to the malignant phenotype of cancer cells. Here, we show that the basal level of NO in breast cells plummets during cancer progression due to reduction of the NO synthase cofactor, BH 4 , under oxidative stress. Importantly, pharmacological deprivation of NO in prepubertal to pubertal animals stiffens the extracellular matrix and induces precancerous lesions in the mammary tissues. These lesions overexpress a fibrogenic cytokine, TGFβ, and an oncogene, ERBB2, accompanied by the occurrence of senescence and stem cell-like phenotype. Consistently, normalization of NO levels in precancerous and cancerous breast cells downmodulates TGFβ and ERBB2 and ameliorates their proliferative phenotype. This study sheds new light on the etiological basis of precancerous breast lesions and their potential prevention by manipulating the basal NO level.

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Nitric oxide triggers mammary gland involution after weaning: remodelling is delayed but not impaired in mice lacking inducible nitric oxide synthase

Zaragozá

Bosch

García

et al. 2010

Biochemical Journal

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During mammary gland involution, different signals are required for apoptosis and tissue remodelling. To explore the role of NO in the involution of mammary tissue after lactation, NOS2 (inducible nitric oxide synthase)-KO (knockout) mice were used. No apparent differences were observed between NOS2-KO and WT (wild-type) animals during pregnancy and lactation. However, upon cessation of lactation, a notable delay in involution was observed, compared with WT mice. NOS2-KO mice showed increased phosphorylation of STAT (signal transducer and activator of transcription) 5 during weaning, concomitant with increased beta-casein mRNA levels when compared with weaned WT glands, both hallmarks of the lactating period. In contrast, activation of STAT3, although maximal at 24 h after weaning, was significantly reduced in NOS2-KO mice. STAT3 and NF-kappaB (nuclear factor kappaB) signalling pathways are known to be crucial in the regulation of cell death and tissue remodelling during involution. Indeed, activation of both STAT3 and NF-kappaB was observed in WT mice during weaning, concomitant with an increased apoptotic rate. During the same period, less apoptosis, in terms of caspase 3 activity, was found in NOS2-KO mice and NF-kappaB activity was significantly reduced when compared with WT mice. Furthermore, the activation of the NF-kappaB signalling pathway is delayed in NOS2-KO mice when compared with WT mice. These results emphasize the role of NO in the fine regulation of the weaning process, since, in the absence of NOS2, the switching on of the cascades that trigger involution is hindered for a time, retarding apoptosis of the epithelial cells and extracellular matrix remodelling.

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Constitutive Coexpression of Nitric Oxide Synthase-1 and Soluble Guanylyl Cyclase in Myoepithelial Cells of Mammary Glands in Mice

Cited by 5 publications

References 33 publications

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

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

Reduced Basal Nitric Oxide Production Induces Precancerous Mammary Lesions via ERBB2 and TGFβ

Nitric oxide triggers mammary gland involution after weaning: remodelling is delayed but not impaired in mice lacking inducible nitric oxide synthase

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