Role of PAR2 in the Development of Lower Urinary Tract Dysfunction

Abstract

Purpose Lower urinary tract symptoms are a common finding in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We reported that the mast cell-tryptase-PAR2 axis plays a critical role in the development of chronic pain in experimental autoimmune prostatitis (EAP), a mouse model of CP/CPPS. We therefore examined whether PAR2 activation mediates lower urinary tract dysfunction. Materials and Methods Functional cystometry was used in male B6 mice along with immunoblots and immunohistochemistry for expression of collagen type I alpha I (COL1A1) and alpha-smooth muscle actin (α-SMA). Flow cytometric analysis was performed on single cell suspensions of the prostate, bladder, lymph nodes and spleen. Results and Conclusions EAP resulted in increased urinary voiding frequency and decreased bladder capacity thirty days after initiation. Concurrently there was increased expression of collagen type I alpha I (COL1A1) and alpha-smooth muscle actin (α-SMA) in the prostates and bladders. In contrast, induction of EAP in PAR2 KO mice did not result in altered urodynamics or increased markers of fibrosis in the prostate or the bladder. Single cell suspensions of the prostate, bladder, lymph nodes and spleen demonstrated that in the absence of PAR2, cellular inflammatory mechanisms were still initiated in EAP but PAR2 expression may be required for maintenance of chronic inflammation. Finally, we demonstrated that antibody mediated PAR2 neutralization normalized urinary voiding frequency and bladder capacity and attenuated chronic pelvic pain. PAR2 activation in the prostate may thus contribute to the development of lower urinary tract dysfunction through proinflammatory as well as profibrotic pathways.

Protease‐activated receptor 2 activates CRAC‐mediated Ca 2+ influx to cause prostate smooth muscle contraction

“…In the murine EAP model of CP/CPPS, there is also increased expression of PAR2 and these mice have associated urinary dysfunction. When PAR2 is neutralized with antibodies, it normalizes voiding frequency and bladder capacity in these CP/CPPS animals . Therefore, based on these studies and our current findings, we think that the limited efficacy of α‐blockers in treating voiding symptoms in patients of CP/CPPS may be due to activation of non‐adrenergic receptors, such as PAR2, which can initiate smooth muscle contractions as α‐adrenergic receptors themselves.…”

“…When PAR2 is neutralized with antibodies, it normalizes voiding frequency and bladder capacity in these CP/CPPS animals. 7,16 Therefore, based on these studies and our current findings, we think that the limited efficacy of α-blockers in treating voiding symptoms in patients of CP/CPPS may be due to activation of non-adrenergic receptors, such as PAR2, which can initiate smooth muscle contractions as α-adrenergic receptors themselves. In fact, Hennenberg et al 38 have alluded to this possibility when they showed that in human prostate tissue endothelin-1 can induce smooth muscle contraction and induce contractile forces that have similar magnitude to those caused by noradrenaline.…”

“…In the colon of patients with irritable bowel syndrome (IBS), increased expression of mast cell tryptase and pain related neuropeptides, such as calcitonin gene related peptide (CGRP), substance P, and vasoactive intestinal peptide (VIP), were positively correlated with increased abdominal pain in these patients . Previously, we have shown in an animal model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), that PAR2 is involved in the pathology of fibrosis and lower urinary tract symptoms (LUTS) . In patients with CP/CPPS, ultrasound evaluation of the bladder neck and posterior urethra show lesions in the fibromuscular stroma that could lead to painful contracture and alter urinary flow .…”

“…6 Previously, we have shown in an animal model of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), that PAR2 is involved in the pathology of fibrosis and lower urinary tract symptoms (LUTS). 7 In patients with CP/CPPS, ultrasound evaluation of the bladder neck and posterior urethra show lesions in the fibromuscular stroma that could lead to painful contracture and alter urinary flow. 8 Incidentally, PAR2 has been shown to play a role in the physiology of smooth muscles in different tissues.…”

Voiding behavior and chronic pelvic pain in two types of rat nonbacterial prostatitis models: Attenuation of chronic pelvic pain by repeated administration of tadalafil

“…Regarding the functional part of the study, we measured only voiding behavior. Additional methodologies such as cystometry or measuring contractility should be included in further studies because EAP in C57BL/6J mice is reported to induce increased voiding frequency and decreased bladder capacity as determined by cystometry . In the present study, we focused on the characterization of two prostatitis models by voiding behavior and chronic pelvic pain.…”