Bladder overactivity induced by psychological stress in female mice is associated with enhanced bladder contractility

West, Eliza G.; Sellers, Donna; Chess-Williams, Russ; McDermott, Catherine

doi:10.1016/j.lfs.2020.118735

Cited by 21 publications

(36 citation statements)

References 43 publications

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“…24 A number of studies have examined lower urinary tract function in these animal models of stress and found bladder dysfunction is a common outcome following a stress protocol. Thus, WAS after only three daily sessions (each lasting 60 minutes) induces an increase in urinary frequency in female mice, 25 and this increases with increasing duration of stress (Figure 1A).…”

Section: Animal Models Of Psychological Stressmentioning

confidence: 94%

“…In the "witness," stress levels measured by changes in circulating corticosterone levels are similar to those of the actual victim undergoing social defeat. Although urinary frequency appears to be a consistent outcome of stress in female rodents, [25][26][27] the outcomes in males are most commonly reduced urinary frequency and urinary retention in most models of stress. 24,28,29 Gender differences are not surprising when the anatomy and physiology of the respective lower urinary tracts are considered.…”

Section: Animal Models Of Psychological Stressmentioning

confidence: 99%

“…A number of these studies have reported enhanced detrusor contraction to muscarinic stimulation in stressed animals. 25 However, this increased responsiveness is not confined to the muscarinic system and enhanced responses to purinergic agonists, but even non-receptor-mediated responses to potassium chloride are enhanced. Two further discoveries may explain this phenomenon.…”

Section: Changes In Detrusor Structure and Functionmentioning

confidence: 99%

“…30 This itself may produce enhanced contractile responses; however, where studies have corrected for tissue mass, contractile responses are still enhanced in detrusor strips from stressed animals. 25 Another explanation for enhanced responses is "calcium sensitization." When detrusor smooth muscle is stimulated to contract, intracellular calcium is elevated, leading to contraction via myosin light chain kinase activation.…”

Section: Changes In Detrusor Structure and Functionmentioning

confidence: 99%

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Chronic psychological stress and lower urinary tract symptoms

Chess-Williams

McDermott

Sellers

et al. 2021

LUTS

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It is well established that lower urinary tract symptoms (LUTS), particularly urinary urgency and incontinence, cause stress and anxiety for patients. However, there is mounting evidence that the relationship between these two factors is bidirectional and that chronic psychological stress itself can result in the development of symptoms such as urinary frequency, urgency, incontinence, and pelvic pain. This review considers the evidence that such a relationship exists and reviews the literature from clinical and animal studies to identify some of the mechanisms that might be involved. Inflammatory responses induced by chronic stress appear to offer the strongest link to bladder dysfunction. There is overwhelming evidence, both in patients and animal models, for a release of pro-inflammatory cytokines and chemokines during periods of chronic stress. Furthermore, cytokines have been shown to cause bladder dysfunction and pain via actions in the central nervous system and locally in the bladder. In the brain and spinal cord, pro-inflammatory cytokines influence the regulation of micturition pathways by corticotropin-releasing factor (CRF) and its receptors, while peripherally cytokines affect bladder function, directly causing detrusor hypertrophy and afferent nerve hypersensitivity. There is little information on which treatments may have most benefit for stressed/anxious patients with LUTS, but animal studies suggest traditional drugs for overactive bladder (solifenacin, mirabegron) are more effective on LUTS than anxiolytic drugs (fluoxetine, imipramine). The preliminary preclinical data for CRF receptor antagonists is not consistent. A clearer understanding of the mechanisms involved in stress-induced LUTS should provide a basis for improved treatment of this condition.

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Section: Animal Models Of Psychological Stressmentioning

confidence: 94%

Section: Animal Models Of Psychological Stressmentioning

confidence: 99%

Section: Changes In Detrusor Structure and Functionmentioning

confidence: 99%

Section: Changes In Detrusor Structure and Functionmentioning

confidence: 99%

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Chronic psychological stress and lower urinary tract symptoms

Chess-Williams

McDermott

Sellers

et al. 2021

LUTS

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“…Like previous studies, we sorted urine output into two classes: primary void spots (PVS; which are typically > 20 µl), or secondary void spots (SVS; those < 20 µl) (40)(41)(42). While the latter are uncommon in control mice (except in the case of aggressive a-males), they increase in animals exhibiting urinary incontinence (i.e., leakage), including mice with experimental cystitis, outlet obstruction, or those exposed to stress (43)(44)(45)(46). Female Piezo1-control mice had ~1 PVS per hour during their active dark phase, but ~1/3 that number was observed during the light phase, when the mice were most often inactive (i.e, resting or sleeping; Figure 4B).…”

Section: Piezo1-ko Mice Exhibit Near-normal Voiding Function and Voiding Behaviormentioning

confidence: 99%

Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception

Dalghi¹,

Ruiz²,

Clayton³

et al. 2021

JCI Insight

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The mechanisms that link visceral mechanosensation to the perception of internal organ status (i.e., interoception) remain elusive. In response to bladder filling, the urothelium releases ATP, which is hypothesized to stimulate voiding function by communicating the degree of bladder fullness to subjacent tissues including afferent nerve fibers. To determine if PIEZO channels function as mechanosensors in these events, we generated conditional urothelial Piezo1-, Piezo2-, and dual Piezo1/2-knockout (KO) mice. While functional PIEZO1 channels were expressed in all urothelial cell layers, Piezo1-KO mice had a limited phenotype. Piezo2 expression was limited to a small subset of superficial umbrella cells, yet male Piezo2-KO mice exhibited incontinence (i.e., leakage) when their voiding behavior was monitored during their active dark phase. Dual Piezo1/2-KO mice had the most significant phenotype, characterized by decreased urothelial responses to mechanical stimulation, diminished ATP release, bladder hypoactivity in anesthetized Piezo1/2-KO females, but not male ones, and urinary incontinence in both male and female Piezo1/2-KO mice during their dark phase, but not inactive light one. Our studies reveal that the urothelium functions in a sex and circadian manner to link urothelial PIEZO1/2 channeldriven mechanotransduction to normal voiding function and behavior, and in the absence of these signals, bladder dysfunction ensues.

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Pathophysiological Mechanisms Involved in Overactive Bladder/Detrusor Overactivity

Chess-Williams

Sellers

2023

Curr Bladder Dysfunct Rep

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Purpose of Review To examine the latest published findings on the pathophysiological mechanisms involved in the development of overactive bladder (OAB) and detrusor overactivity (DO), and to identify common pathways linked to the risk factors associated with these conditions. Recent Findings Evidence is accumulating, both clinical and experimental, that many of the factors linked to the development of OAB/DO, including ageing, bladder outlet obstruction, psychological stress, and obesity are associated with reduced bladder blood flow. This induces local tissue inflammation with cytokine release and enhanced oxidative stress, ultimately resulting in altered detrusor sensitivity, detrusor hypertrophy and fibrosis, together with afferent hypersensitivity. These mechanisms would explain the symptoms of urgency and frequency observed in OAB patients. Although not a characteristic of OAB, undetected low level bacterial infections of the bladder have been proposed to explain the OAB symptoms in patients resistant to standard treatments. In this condition, inflammatory responses without reductions in perfusion activate the inflammatory pathways. Summary Evidence is mounting that poor bladder perfusion and local inflammatory responses are central mechanisms involved in the development of OAB/DO. As our understanding of these pathophysiological mechanisms advances, new avenues for drug development will be identified and ultimately treatment may become more individualized depending on the particular pathway involved and the drugs available.

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Bladder overactivity induced by psychological stress in female mice is associated with enhanced bladder contractility

Cited by 21 publications

References 43 publications

Chronic psychological stress and lower urinary tract symptoms

Chronic psychological stress and lower urinary tract symptoms

Functional roles for PIEZO1 and PIEZO2 in urothelial mechanotransduction and lower urinary tract interoception

Pathophysiological Mechanisms Involved in Overactive Bladder/Detrusor Overactivity

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