Sex differences in lower urinary tract function in mice with or without spinal cord injury

Abstract

ObjectivesWe examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI).MethodsSCI was induced by Th8−9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6‐S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme‐linked immunosorbent assay.ResultsSex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice.ConclusionsWe demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6‐S1 DRG and NGF in the bladder could be involved in SCI‐induced lower urinary tract dysfunction in both sexes of mice.

Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including β3-Adrenoceptor Agonists -Basic Research Perspectives-

“…NGF stimulates the proliferation and survival of target neurons [ 50 ], and bladder NGF also lowers the threshold of TRPV1 [ 51 ]. Excessive NGF expression is involved in OAB pathogenesis by influencing bladder dysfunction through these mechanisms [ 52 ]. Some studies have found that unidentified inhibitory substances other than NO, cyclooxygenase, catecholamine, adenosine, and GABA (γ-Aminobutyric acid) are released from the urothelium upon stimulation of muscarinic receptors [ 53 , 54 ].…”

Ablation of the integrin CD11b mac-1 limits deleterious responses to traumatic spinal cord injury and improves functional recovery in mice

“…All surgical and experimental procedures in this study were performed under protocols approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Maryland School of Medicine. To reduce the risk of bladder infection (32,33), we only used female mice in this study. Young adult (10-12 weeks) female CD11b KO mice were obtained from Dr. Li Zhang's lab and maintained in the UMB animal facility.…”

Sexual Dimorphism of Spinal Neural Circuits Controlling the Mouse External Urethral Sphincter With and Without Spinal Cord Injury

“…In males, voiding is accompanied by EUS-electromyography (EUS-EMG) busting and rhythmic 5-7 Hz EUS contractions actively pumping out portions of urine. In females, voiding occurs during a series of smooth waves of urethra relaxation, allowing passive release of urine driven by intravesical pressure (Hashimoto et al 2024) Thus, difference in mechanisms of voiding may explain the observed fact of much easier manual emptying of the BL in females than in males before reflex voiding recovers after SCI (personal observation). Restoration of reflex voiding in females also occurs earlier than in males (Saito et al 2021), which is consistent with the notion of functional dimorphism as a consequence of anatomical dimorphism.…”