The bladder has the capability of maintaining low muscle excitability and low intravesical pressure throughout most of the filling period. Loss of this ability to moderate muscle excitability is associated with development of detrusor overactivity (DO). Detrusor smooth muscle cells (SMC) tend to be activated by stretch due to expression of stretch-activated non-selective cation channels. So other cells, such as neurons or interstitial cells appear to be necessary to restrain development of SMC excitability during filling. Recently, we discovered and characterized a novel control mechanism that is intrinsic to detrusor muscles, provided by PDGFR?+ interstitial cells and regulates detrusor excitability. PDGFR?+ cells have been identified and are abundant in human, guinea pig and mouse detrusor muscles. The regulatory mechanism is composed of the following molecular and functional elements: 1) PDGFR?+ cells express SK3 channels (Kcnn3) and high current density due to SK channels. 2) SK channels in PDGFR?+ cells exert membrane potential-stabilizing effects on electrically coupled SMC. 3) TRPV4 channels, also expressed by PDGFR?+ cells, provide a stretch-dependent source of Ca2+ that activates SK channels during filling. In phase with loss of PDGFR?+ cells is the development of DO, as shown by the development of excessive Ca2+ transients in SMC bundles and transient contractions during bladder filling. From preliminary experiments, we have discovered that significant damage to PDGFR?+ cells occurs after spinal cord injury (SCI) in an animal model that is known also to develop DO. We have also discovered a mechanism for the damage to PDGFR?+ cells and a means of rescuing the cells after SCI. PDGFR?+ cells express neurotrophin receptors (predominantly TrkB) and SCI are associated with reduced expression of TrkB. Reduced TrkB signaling has been associated with apoptosis in neural and non-neural cells, and preliminary experiments show that genes related to apoptotic signaling are enhanced in PDGFR?+ cells after SCI. We also found that localized treatment of the detrusor with a TrkB agonist, shortly after SCI, rescued the PDGFR?+ cell phenotype and prevented the development of DO. Therefore, in the current proposal we will pursue the following overarching hypothesis: loss or defects in PDGFR?+ cells or in key molecular components responsible for the inhibitory regulation provided by PDGFR?+ cells leads to detrusor dysfunction and development of detrusor overactive phenotype. Completion of the specific aims of this study will provide exciting novel insights into how the bladder is regulated during filling and how dysfunction might be managed after SCI by showing: i) PDGFR?+ cells are critical regulators of detrusor excitability during filling; ii) loss or damage to these cells leads to an DO phenotype; iii) restoration of PDGFR?+ cells can rescue normal responses to bladder filling.
The bladder has the capability of restraining contractions as it fills with urine. Loss of the ability to moderate muscle contractions is associated with development of overactive bladder. This project has discovered a novel, intrinsic mechanism in bladder muscles to control unwanted contractile behavior.
