ANO1 in urethral SMCs contributes to sex differences in urethral spontaneous tone

2020 ◽  
Vol 319 (3) ◽  
pp. F394-F402
Author(s):  
Defang Chen ◽  
Wen Meng ◽  
Ling Shu ◽  
Shuang Liu ◽  
Yongzhong Gu ◽  
...  
Keyword(s):  
Sex Differences ◽  
Urinary Incontinence ◽  
Molecular Mechanisms ◽  
Male Mice ◽  
Anoctamin 1 ◽  
Anatomic Structure ◽  
Female Mice ◽  
Spontaneous Tone ◽  
Intracellular Ca ◽  
Urethral Smooth Muscle

Stress urinary incontinence (SUI) is more common in women than in men, and sex differences in anatomic structure and physiology have been suggested as causes; however, the underlying cellular and molecular mechanisms remain unclear. The spontaneous tone (STT) of the urethra has been shown to have a fundamental effect on preventing the occurrence of SUI. Here, we investigated whether the urethral STT exhibited sex differences. First, we isolated urethral smooth muscle (USM) and detected STT in female mice and women. No STT was found in male mice or men. Furthermore, caffeine induced increased contractility and intracellular Ca2+ concentration in urethrae from female mice compared with male mice. EACT [an N-aroylaminothiazole, anoctamin-1 (ANO1) activator] elicited increased intracellular Ca2+ concentration and stronger currents in female mice than in male mice. Moreover, ANO1 expression in single USM cells from women and female mice was almost twofold higher than that found in cells from men and male mice. In summary, ANO1 in USM contributes to sex differences in urethral spontaneous tone. This finding may provide new guidance for the treatment of SUI in women and men.

Sex Differences in the Relation Between Frailty and Endothelial Dysfunction in Old Mice

2021 ◽  
Author(s):  
Jazmin A Cole ◽  
Mackenzie N Kehmeier ◽  
Bradley R Bedell ◽  
Sahana Krishna Kumaran ◽  
Grant D Henson ◽  
...  
Keyword(s):  
Sex Differences ◽  
Endothelial Function ◽  
Vascular Function ◽  
Mesenteric Artery ◽  
Frailty Index ◽  
Mesenteric Arteries ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Age Related

Abstract Vascular endothelial function declines with age on average, but there is high variability in the magnitude of this decline within populations. Measurements of frailty, known as frailty index (FI), can be used as surrogates for biological age, but it is unknown if frailty relates to the age-related decline in vascular function. To examine this relation, we studied young (4-9 months) and old (23-32 months) C57BL6 mice of both sexes. We found that FI was greater in old compared with young mice, but did not differ between old male and female mice. Middle cerebral artery (MCA) and mesenteric artery endothelium-dependent dilation (EDD) also did not differ between old male and female mice; however, there were sex differences in the relations between FI and EDD. For the MCA, FI was inversely related to EDD among old female mice, but not old male mice. In contrast, for the mesenteric artery, FI was inversely related to EDD among old male mice, but not old female mice. A higher FI was related to a greater improvement in EDD with the superoxide scavenger TEMPOL in the MCAs for old female mice and in the mesenteric arteries for old male mice. FI related to mesenteric artery gene expression negatively for extracellular superoxide dismutase (Sod3) and positively for interleukin-1β (Il1b). In summary, we found that the relation between frailty and endothelial function is dependent on sex and the artery examined. Arterial oxidative stress and pro-inflammatory signaling are potential mediators of the relations of frailty and endothelial function.

scholarly journals Sex differences in renal and metabolic responses to a high-fructose diet in mice

2015 ◽  
Vol 308 (5) ◽  
pp. F400-F410 ◽  
Author(s):  
Nikhil Sharma ◽  
Lijun Li ◽  
C. M. Ecelbarger
Keyword(s):  
Sex Differences ◽  
Glucose Transporter ◽  
Collecting Duct ◽  
Urine Volume ◽  
Thick Ascending Limb ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
High Fructose Diet ◽  
High Fructose

High fructose intake has been associated with increased incidences of renal disease and hypertension, among other pathologies. Most fructose is cleared by the portal system and metabolized in the liver; however, systemic levels of fructose can rise with increased consumption. We tested whether there were sex differences in the renal responses to a high-fructose diet in mice. Two-month-old male and female C57BL6/129/SV mice ( n = 6 mice per sex per treatment) were randomized to receive control or high-fructose (65% by weight) diets as pelleted chow ad libitum for 3 mo. Fructose feeding did not significantly affect body weight but led to a 19% and 10% increase in kidney weight in male and female mice, respectively. In male mice, fructose increased the expression (∼50%) of renal cortical proteins involved in metabolism, including glucose transporter 5 (facilitative fructose transporter), ketohexokinase, and the insulin receptor (β-subunit). Female mice had lower basal levels of glucose transporter 5, which were unresponsive to fructose. However, female mice had increased urine volume and plasma K+ and decreased plasma Na+ with fructose, whereas male mice were less affected. Likewise, female mice showed a two- to threefold reduction in the expression Na+-K+-2Cl− cotransporter 2 in the thick ascending limb and aquaporin-2 in the collecting duct with fructose relative to female control mice, whereas male mice had no change. Overall, our results support greater proximal metabolism of fructose in male animals and greater distal tubule/collecting duct (electrolyte homeostasis) alterations in female animals. These sex differences may be important determinants of the specific nature of pathologies that develop in association with high fructose consumption.

scholarly journals Oral prescription opioid-seeking behavior in male and female mice

2019 ◽  
Author(s):  
Alysabeth G. Phillips ◽  
Dillon J. McGovern ◽  
Soo Lee ◽  
Kyu Ro ◽  
David T. Huynh ◽  
...  
Keyword(s):  
Sex Differences ◽  
Oral Drug ◽  
Prescription Opioid ◽  
Male Mice ◽  
Self Administration ◽  
Female Mice ◽  
Seeking Behavior ◽  
Opioid Users ◽  
Psychomotor Stimulation

AbstractA significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug-seeking. However, intravenous models may not model oral users, and the preference to self-administer orally appears to be partially influenced by the user’s sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated robust cue-induced reinstatement. In separate mice we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior in the absence of postprandial or prior water self-administration training. During self-administration, we found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal steroid studies were performed in which we found divergent responses where ovariectomy enhanced and orchiectomy suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that 1) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, 2) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and 3) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.

scholarly journals Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice

2020 ◽  
Author(s):  
Diana Tavares-Ferreira ◽  
Pradipta R. Ray ◽  
Ishwarya Sankaranarayanan ◽  
Galo L. Mejia ◽  
Andi Wangzhou ◽  
...  
Keyword(s):  
Sex Differences ◽  
Cortical Neurons ◽  
Affinity Purification ◽  
Male Mice ◽  
Protective Behaviors ◽  
Pain Mechanisms ◽  
Female Mice ◽  
Mechanistic Basis ◽  
High Doses ◽  
Neuronal Functions

ABSTRACTBackgroundThere are clinically relevant sex differences in acute and chronic pain mechanisms, but we are only beginning to understand their mechanistic basis. Transcriptome analyses of rodent whole dorsal root ganglion (DRG) have revealed sex differences, mostly in immune cells. We examined the transcriptome and translatome of the mouse DRG with the goal of identifying sex differences.MethodsWe used Translating Ribosome Affinity Purification (TRAP) sequencing and behavioral pharmacology to test the hypothesis that nociceptor (Nav1.8 expressing neurons) translatomes would differ by sex.ResultsWe found 66 genes whose mRNA were sex-differentially bound to nociceptor ribosomes. Many of these genes have known neuronal functions but have not been explored in sex differences in pain. We focused on Ptgds, which was increased in female mice. The mRNA encodes the prostaglandin D2 (PGD2) synthesizing enzyme. We observed increased Ptgds protein and PGD2 in female mouse DRG. The Ptgds inhibitor AT-56 caused intense pain behaviors in male mice but was only effective at high doses in females. Conversely, female mice responded more robustly to another major prostaglandin, PGE2, than did male mice. Ptgds protein expression was also higher in female cortical neurons, suggesting DRG findings may be generalizable to other nervous system structures.ConclusionsNociceptor TRAP sequencing (TRAP-seq) reveals unexpected sex differences in one of the oldest known nociceptive signaling molecule families, the prostaglandins. Our results demonstrate that translatome analysis reveals physiologically relevant sex differences important for fundamental protective behaviors driven by nociceptors.

scholarly journals Microthrombi Correlates With Infarction and Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice

Stroke ◽  
2020 ◽  
Vol 51 (7) ◽  
pp. 2249-2254 ◽  
Author(s):  
Ari Dienel ◽  
Remya Ammassam Veettil ◽  
Sung-Ha Hong ◽  
Kanako Matsumura ◽  
Peeyush Kumar T. ◽  
...  
Keyword(s):  
Sex Differences ◽  
Subarachnoid Hemorrhage ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Behavioral Performance ◽  
Large Artery ◽  
Male Mice ◽  
Functional Deficits ◽  
Female Mice ◽  
Correlation Analyses

Background and Purpose: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. Methods: Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. Results: Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. Conclusions: We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.

scholarly journals Sex differences in adaptive downregulation of pre-macula densa sodium transporters with ANG II infusion in mice

2010 ◽  
Vol 298 (1) ◽  
pp. F187-F195 ◽  
Author(s):  
Swasti Tiwari ◽  
Lijun Li ◽  
Shahla Riazi ◽  
Veerendra K. Madala Halagappa ◽  
Carolyn M. Ecelbarger
Keyword(s):  
Sex Differences ◽  
Plasma Testosterone ◽  
Sodium Reabsorption ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Sodium Transporters ◽  
Pressure Natriuresis

An increase in blood pressure (BP) due to angiotensin II (ANG II) infusion or other means is associated with adaptive pressure natriuresis due to reduced sodium reabsorption primarily in proximal tubule (PT) and thick ascending limb (TAL). We tested the hypothesis that male and female mice would show differential response to ANG II infusion with regard to the regulation of the protein abundance of sodium transporters in the PT and TAL and that these responses would be modulated by aging. Young (∼3 mo) and old (∼21 mo) male and female mice were infused with ANG II at 800 ng·kg body wt−1·min−1 by osmotic minipump for 7 days or received a sham operation. ANG II increased mean arterial pressure (MAP), measured by radiotelemetry, significantly more in male mice of both ages (increased ∼30–40 mmHg), compared with females (increased ∼15–25 mmHg). On day 1, MAP was also significantly increased in old mice, relative to young ( P = 0.01). ANG II infusion was associated with a significant decline in plasma testosterone (to <30% of control male) in male mice and rise in young female mice (to 478% of control female). No sex differences were found in the upregulation of the sodium hydrogen exchanger abundance on Western blots observed with ANG II infusion or the downregulation of the sodium phosphate cotransporter; however, aging did impact on some of these changes. Male mice (especially young) also had significantly reduced levels of the TAL bumetanide-sensitive Na-K-2Cl cotransporter (to 60% of male control), while young females showed an increase (to 126% of female control) with ANG II infusion. These sex differences do not support impaired pressure natriuresis in male mice, but might reflect a greater need and attempt to mount an appropriately BP-metered natriuretic response by additional downregulation of TAL sodium reabsorption.

Abstract 612: ACE2-Independent Sex Differences In Oxidative Stress

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Jan Wysocki ◽  
Karla Evora ◽  
Moody Salem ◽  
Christoph Maier ◽  
Minghao Ye ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sex Differences ◽  
Nadph Oxidase ◽  
Total Protein ◽  
Oxidase Activity ◽  
Kidney Injury ◽  
Ang Ii ◽  
Male Mice ◽  
Nadph Oxidase Activity ◽  
Female Mice

Many of the pathophysiological effects of angiotensin II (Ang II) are attributed to its stimulation of NADPH oxidases and the consequent production of reactive oxygen species. Female sex has generally lower cardiovascular morbidity and is also less susceptible to kidney injury than males. The basis of these phenomena is not well understood but it is possible that sex-differential regulation of oxidative stress through activation of the RAS and its key effector, Ang II, plays an important contributor role. Here we hypothesized that Ang II levels are higher in male mice and that this is associated with sex-differences in kidney levels of ACE2, an Ang II-degrading enzyme abundantly expressed in the kidney. Parameters of oxidative stress such as, NADPH oxidase activity and malondialdehyde levels (MDA) were measured in kidneys from female and age-matched male C57BL6 mice. At 40 weeks of age, NADPH oxidase activity (p<0.01) and MDA levels (p<0.05) were significantly lower in female than in male mice. Female mice had lower kidney levels of the pro-oxidant peptide, Ang II (0.94±0.19 vs. 1.66±0.17 fmol/mg total protein, p<0.05, respectively). The difference in kidney Ang II levels between females and males was also observed in the face of complete ACE2 genetic deficiency (1.08±0.16 vs 1.97±0.25 fmol/mg total protein, p<0.05, respectively). Consistent with kidney Ang II levels, urinary Ang II levels measured in urines from female WT mice were also significantly lower than in male WT mice (23.6±2.2 vs. 47.9±8.8 pg/mg creatinine, p<0.05) despite significantly higher levels of urinary ACE2 activity in male mice as compared to female mice (7.0±0.5 vs. 3.6±0.3, p<0.01, respectively). Female mice have lower basal levels of kidney oxidative stress than males and exhibit lower levels of kidney and urinary Ang II. The mechanism involved in sex differences in the levels of kidney and urine Ang II does not appear to depend on ACE2.

scholarly journals Mechanisms of sex differences in exercise capacity

2019 ◽  
Vol 316 (6) ◽  
pp. R832-R838 ◽  
Author(s):  
Marko Oydanich ◽  
Denis Babici ◽  
Jie Zhang ◽  
Nicole Rynecki ◽  
Dorothy E. Vatner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sex Differences ◽  
Nitric Oxide Synthase ◽  
Myosin Heavy Chain ◽  
Exercise Capacity ◽  
Heavy Chain ◽  
Type I ◽  
Male Mice ◽  
Female Mice ◽  
Oxide Synthase

Sex differences are an important component of National Institutes of Health rigor. The goal of this investigation was to test the hypothesis that female mice have greater exercise capacity than male mice, and that it is due to estrogen, nitric oxide, and myosin heavy chain expression. Female C57BL6/J wild-type mice exhibited greater ( P < 0.05) maximal exercise capacity for running distance (489 ± 15 m) than age-matched male counterparts (318 ± 15 m), as well as 20% greater work to exhaustion. When matched for weight or muscle mass, females still maintained greater exercise capacity than males. Increased type I and decreased type II myosin heavy chain fibers in the soleus muscle from females are consistent with fatigue resistance and better endurance in females compared with males. After ovariectomy, female mice no longer demonstrated enhanced exercise, and treatment of male mice with estrogen resulted in exercise capacity similar to that of intact females (485 ± 37 m). Nitric oxide synthase, a downstream target of estrogen, exhibited higher activity in female mice compared with male mice, P < 0.05, whereas ovariectomized females exhibited nitric oxide synthase levels similar to males. Nitric oxide synthase activity also increased in males treated with chronic estrogen to levels of intact females. Nitric oxide synthase blockade with Nω-nitro-l-arginine methyl ester eliminated the sex differences in exercise capacity. Thus estrogen, nitric oxide, and myosin heavy chain expression are important mechanisms mediating the enhanced exercise performance in females.

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