Sex difference in the expression and regulation of nitric oxide synthase gene in the rat preoptic area

Ishihara, Tamaki; Orikasa, Chitose; Araki, Tsutomu; Sakuma, Yasuo

doi:10.1016/s0168-0102(02)00025-1

Cited by 19 publications

(16 citation statements)

References 32 publications

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“…This was independent of genotype suggesting a potential developmental gonad independence of this characteristic. Similarly, in the more rostral region of AVPV, males of both genotypes also had significantly higher number of nNOS immunopositive cells and larger nNOS immunoreactive area (data not shown) than females in agreement with a study in rats (Ishihara et al, 2002). The larger difference between WT males and females in comparison to SF-1 KO males and females in the AVPV region might suggest that the sex difference initially produced by the action of genes on sex chromosomes might increase upon developmental exposure to sex steroids.…”

Section: Figure 11supporting

confidence: 90%

Sex differences in brain developing in the presence or absence of gonads

Büdefeld

Grgurevic

Tobet

et al. 2008

Developmental Neurobiology

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Brain sexual differentiation results from the interaction of genetic and hormonal influences. This study used a unique agonadal mouse model to determine relative contributions of genetic and gonadal hormone influences in the differentiation of selected brain regions. SF-1 knockout (SF-1 KO) mice are born without gonads and adrenal glands and are not exposed to endogenous sex steroids during fetal/neonatal development. Consequently, male and female SF-1 KO mice are born with female external genitalia and if left on their own, die shortly after birth due to adrenal insufficiency. In this study, SF-1 KO mice were rescued by neonatal adrenal transplantation to examine their brain morphology in adult life. To determine potential brain loci that might mediate functional sex differences, we examined the area and distribution of immunoreactive calbindin and neuronal nitric oxide synthase in the preoptic area (POA) and ventromedial nucleus of the hypothalamus, two areas previously reported to be sexually dimorphic in the mammalian brain. A sex difference in the positioning of cells containing immunoreactive calbindin in a group within the POA was clearly gonad dependent based on the elimination of the sex difference in SF-1 KO mice. Several other differences in the area of ventromedial hypothalamus and in POA were maintained in male and female SF-1 KO mice, suggesting gonad-independent genetic influences on sexually dimorphic brain development.

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Section: Figure 11supporting

confidence: 90%

Sex differences in brain developing in the presence or absence of gonads

Büdefeld

Grgurevic

Tobet

et al. 2008

Developmental Neurobiology

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“…After ovariectomy, nNOS staining was more evident throughout both the cortical and medullary regions of the kidney. The influence of estrogen on the expression of nNOS is not as well characterized as that for eNOS, and there is no clear consensus on the regulatory role for estrogen, particularly within the kidney (14,16,20,27,29,38). To our knowledge, the present study is the first to assess the effects of chronic treatment with a nNOS inhibitor in female hypertensive rats.…”

Section: Discussionmentioning

confidence: 88%

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

Yamaleyeva¹,

Gallagher²,

Vinsant³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Yamaleyeva LM, Gallagher PE, Vinsant S, Chappell MC. Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats. Am J Physiol Regul Integr Comp Physiol 292: R819 -R826, 2007. First published October 5, 2006; doi:10.1152/ajpregu.00389.2006.-Estrogen depletion markedly exacerbates hypertension in female congenic mRen2.Lewis rats, a model of tissue renin overexpression. Because estrogen influences nitric oxide synthase (NOS) and NO may exert differential effects on blood pressure, the present study investigated the functional expression of NOS isoforms in the kidney of ovariectomized (OVX) mRen2.Lewis rats. OVX-mRen2.Lewis exhibited an increase in systolic blood pressure (SBP) of 171 Ϯ 5 vs. 141 Ϯ 7 mmHg (P Ͻ 0.01) for intact littermates. Renal cortical mRNA and protein levels for endothelial NOS (eNOS) were reduced 50 -60% (P Ͻ 0.05) and negatively correlated with blood pressure. In contrast, cortical neuronal NOS (nNOS) mRNA and protein levels increased 100 to 300% (P Ͻ 0.05). In the OVX kidney, nNOS immunostaining was more evident in the macula densa, cortical tubules, and the medullary collecting ducts compared with the intact group. To determine whether the increase in renal nNOS expression constitutes a compensatory response to the reduction in renal eNOS, we treated both intact and OVX mRen2.Lewis rats with the selective nNOS inhibitor L-VNIO from 11 to 15 wk of age. The nNOS inhibitor reduced blood pressure in the OVX group (185 Ϯ 3 vs. 151 Ϯ 8 mmHg, P Ͻ 0.05), but pressure was not altered in the intact group (146 Ϯ 4 vs. 151 Ϯ 4 mmHg). In summary, exacerbation of blood pressure in the OVX mRen2.Lewis rats was associated with the discoordinate regulation of renal NOS isoforms. Estrogen sensitivity in this congenic strain may involve the influence of NO through the regulation of both eNOS and nNOS. endothelial nitric oxide synthase; estrogen; hypertension; aldosterone; angiotensin II; renin THE PROTECTIVE ROLE OF ESTROGEN in cardiovascular disease remains a highly controversial and complex area of study, particularly given the recent findings of the Women's Health Initiative (WHI) study. Although experimental and clinical data support the beneficial actions of estrogen, both the WHI and the Heart and Estrogen Replacement Study follow-up (HERS II) studies concluded that there was no cardioprotective benefit for estrogen replacement in older women with underlying cardiovascular disease (19, 39). Indeed, the incidence for ischemic stroke and dementia were higher for this population of postmenopausal women receiving either estrogen or combined hormone replacement therapy (40, 41). The results of WHI and HERS were surprising, in part, due to the generally accepted view that estrogen has beneficial actions on nitric oxide (NO), as well as an inhibitory influence on the components of the renin-angiotensin-aldosterone system (RAAS), including ACE and the angiotensin type 1 (AT1) receptor (6,12,17,26,33,45).Our studies in the congenic mRen2.Lewis strain of hypertensive rats ...

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“…It has been shown that estrogen acting on ER upregulates nNOS in the brain and that this effect appears to be regionally and/or receptor specific (6,18,22,23). To confirm the important role of estrogen, Sica et al (44) observed a significant decrease of NOS immunoreactive cells in the medial preoptic area of aromatase knockout male mice.…”

Section: Discussionmentioning

confidence: 99%

Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide

Xue¹,

Singh²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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.-The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry im-), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of L-NAME augmented the pressor effects of systemic ANG II in females (⌬21.5 Ϯ 2.2 vs. ⌬9.2 Ϯ 1.5 mmHg) but not in males (⌬29.4 Ϯ 2.5 vs. ⌬30.1 Ϯ 2.5 mmHg). Central administration of, a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (⌬17.5 Ϯ 3.2 vs. ⌬9.2 Ϯ 1.5 mmHg). In gonadectomized mice, central L-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central L-NAME-or L-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were ϳ12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to ϳ51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a protective role against ANG II-induced hypertension in female mice. sex hormone; nitric oxide/nitric oxide synthase; blood pressure NITRIC OXIDE (NO) and angiotensin II (ANG II) are important agents that regulate arterial blood pressure (BP). Vasoconstriction produced by sympathoexcitatory effects contributes to ANG II-induced pressor responses (13, 17). Conversely, NO has a hypotensive action via vasodilation and sympathoinhibition (36, 39). It has been shown that interactions between ANG II and NO occur in a variety of tissues, including the central nervous system (CNS) (40, 58). For example, microinjection of either an NO synthase (NOS) inhibitor or ANG II into the lateral ventricle or the paraventricular nucleus (PVN) increases the discharge of renal sympathetic nerves and elevates arterial BP and heart rate (HR) (25, 28, 52). Central or peripheral blockade of NOS potentiates or prolongs the pressor response to ANG II (9, 31). Conversely, overexpression of neuronal NOS (nNOS) within the PVN by adenoviral gene transfer significantly attenuates ANG II pressor responses (28).There is evidence from human and animal studies that hypertension is delayed and attenuated in females compared with males (11). Previous studies from our laboratory (54) have sh...

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Sex difference in the expression and regulation of nitric oxide synthase gene in the rat preoptic area

Cited by 19 publications

References 32 publications

Sex differences in brain developing in the presence or absence of gonads

Sex differences in brain developing in the presence or absence of gonads

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

Protective actions of estrogen on angiotensin II-induced hypertension: role of central nitric oxide

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