Introduction: Partial bladder outflow obstruction (pBOO) causes remodeling of the bladder wall, with smooth muscle hypertrophy and an excessive deposition of extracellular matrix (ECM) proteins, leading to bladder fibrosis. Our understanding of the pathophysiology of this process is limited and no effective treatment to prevent or reverse bladder fibrosis exists. Microfibrillar-associated protein 4 (MFAP4) is an ECM glycoprotein, localized to elastic fiber-rich regions. It binds ECM components including elastin and collagen and contributes to the process of elastogenesis in healthy tissues. Emerging data suggest the involvement of MFAP4 in the pathogenesis of disease-induced tissue remodeling, including fibrosis. To determine its value as a potential therapeutic target, we compared MFAP4 expression in sham-operated bladders to bladders 6 weeks following pBOO. MFAP4 levels were then correlated with bladder function. Methods: Partial BOO, was induced in 9 male Sprague Dawley rats, 5 underwent sham surgery. Six weeks following surgery, rats were placed in a metabolic cage overnight to record 12-hour micturition frequency and volume per void. Gene expression levels of MFAP4, alpha-smooth muscle actin (a-SMA) and collagen I were quantified in the bladder tissue using real-time PCR Results: The bladder/body ratio was significantly higher in the pBOO group (0.07±0.04) when compared to the SHAM group (0.024±0.003). Obstructed rats with increased MFAP4 expression demonstrated an increase in a-SMA expression. No significant increase in collagen I levels was recorded in the pBOO group. Animals with bladder overactivity as determined by frequent low volume micturitions (=4 micturitions with <0.1 mL per void/12 hours) had higher MFAP4 expression than animals in the SHAM group, which exhibited normal micturition pattern. Conclusions: These initial observations show that pBOO lasting 6 weeks results in detrusor hypertrophy. Although bladder wall fibrosis did not develop within the 6-week timeframe, our data suggest that bladder remodeling following pBOO is associated with increased MFAP4 levels and that MFAP4 might be involved in the pathogenesis of pBOO-induced bladder dysfunction. Experiments addressing processes extending beyond 6 weeks post-pBOO and possible involvement of MFAP4 in their pathophysiology are ongoing. SOURCE OF Funding: Odense University hospital
