SCI-induced and partial bladder outlet obstruction mouse models. Molecular characterization of obstructive and neurogenic lower urinary tract dysfunction (LUTD) in SCI-induced and partial bladder outlet obstruction mouse models

We examined bladder function following spinal cord injury (SCI) by repeated urodynamic investigation (UDI) including external urethral sphincter (EUS) electromyography (EMG) in awake restrained mice and correlated micturition parameters to gene expression and morphological changes in the bladder. A partial bladder outlet obstruction (pBOO) model was used for comparison to elucidate the common and specific features of obstructive and neurogenic lower urinary tract dysfunction (LUTD). Thirty female C57Bl/6J mice in each study were implanted with a bladder catheter and additionally with electrodes next to the EUS in the SCI study. UDI assessments were performed weekly during 8 weeks followed by bladder harvest and histological and transcriptome analysis. SCI mice developed detrusor-sphincter dyssynergia (DSD) one week after injury with high pressure oscillations and a significantly increased maximal bladder pressure Pmax, and were unable to void spontaneously during the whole observation period. They showed an increased bladder to bodyweight ratio, bladder fibrosis and transcriptome changes indicative of extracellular matrix remodeling and alterations of neuronal signaling and muscle contraction. In contrast, pBOO led to a significantly increased Pmax after one week, which normalized at later time points. Increased bladder to bodyweight ratio, and pronounced gene expression changes involving immune- and inflammatory pathways were observed 7 weeks after pBOO. Comparative transcriptome analysis of SCI and pBOO bladders revealed the activation of Wnt and TGF-beta signaling in both the neurogenic and obstructive LUTD, and highlighted FGF2 as a major transcription factor up-regulated during organ remodeling. We conclude that SCI-induced DSD in mice results in neurogenic LUTD with profound changes in neuronal signaling and muscle contractility leading to bladder fibrosis. In the similar time frame, significant bladder remodeling following pBOO allowed for functional compensation preserving normal micturition parameters.