The Role of TRPV4 in Repeated Variate Stress-Induced Increases in Voiding Frequency and Somatic Sensitivity in Male and Female Mice.

Psychological stress is a known precipitant of lower urinary tract (LUT) dysfunction and can exacerbate pelvic pain, yet the underlying mechanisms remain incompletely understood. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel expressed in LUT tissues and associated afferent circuits, is positioned to couple stress-related signaling to changes in voiding function. We tested the hypothesis that TRPV4 is required for repeated variate stress (RVS)-evoked bladder dysfunction and contributes to stress-associated somatic hypersensitivity and anxiety-like behavior. Male and female wild-type (WT) and Trpv4 knockout (KO) mice underwent RVS and were assessed using conscious cystometry, void spot assay (VSA), mechanical sensitivity testing (pelvic and hindpaw), and behavioral assays (open field, elevated plus maze). RVS produced sex- and tissue-specific regulation of Trpv4 transcripts LUT tissues. In WT mice, RVS induced bladder overactivity in both sexes, characterized by increased voiding frequency and reduced intermicturition interval. These stress-induced changes were absent in Trpv4 KO mice, demonstrating that TRPV4 is required for stress-evoked bladder dysfunction. Bladder pressure endpoints revealed additional sex-dependent effects in WT but not Trpv4 KO mice. VSA identified sex-specific spontaneous voiding changes that did not uniformly parallel cystometric measures, indicating complementary sensitivity of provoked and unprovoked assays. Despite protection from stress-associated bladder dysfunction, Trpv4 KO mice exhibited increased pelvic and hindpaw mechanical sensitivity following RVS. Behavioral testing revealed sex-dependent differences in stress resilience. These findings identify TRPV4 as a key mediator of stress-induced bladder overactivity and demonstrate a dissociation between referred mechanical pain outcomes in Trpv4 KO mice.