Approximately 43 million men and 71 million women suffer from troublesome lower urinary tract symptoms (LUTS) in the US alone, representing a significant public health burden. Among the many different origins of LUTS, inflammation in the bladder wall alters urothelial signaling, detrusor contractility, and bladder wall biomechanics – all of which could disrupt normal storage and voiding function. The Mas-related G protein-coupled receptor B2 (Mrgprb2) is an orphan receptor traditionally believed to be expressed on mast cells that drives “pseudo-inflammation” through IgE-independent degranulation of mast cells. The exact role of Mrgprb2 in altering bladder function is unknown. Thus, this dissertation pursues the following hypothesis: Mrgprb2 receptor activation promotes Matrix metalloprotease-mediated collagen degradation leading to altered mechanical compliance. We observed that the Mrgprb2 agonist, compound 48/80, rapidly increases mechanical compliance of whole bladders during ex vivo filling while paradoxically increasing detrusor excitability. Compound 48/80 also caused overactivity when administered intravesically during conscious cystometry. Unexpectedly, these changes persisted in mast cell-deficient mice, suggesting that the effects of compound 48/80 are independent of mast cells. Visualization of collagen fibers within the wall showed that Mrgprb2 agonism leads to a significant reduction in bladder wall thickness combined with a disruption in MMP-2/TIMP-2 balance hence it is likely that the former is a product of the latter. Also, collagen remodeling still occurs in the absence of urothelial permeabilization. Together, these findings suggest that the material properties of the bladder wall are more labile than we imagined. Mrgprb2 activation in the bladder wall can lead to rapid and profound changes in compliance mediated by imbalances in the MMP-TIMP family of enzymes. Understanding the pathophysiology of this mechanism is of significance since it uncovers various druggable targets for inflammatory LUTS outside of mast cell degranulation. This dissertation provides novel insights into the critical role of Mrgprb2 in driving rapid changes in bladder function, thereby contributing to a better understanding of the consequences of pro-inflammatory pathway activation in the urinary bladder.
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