Pelvic organ prolapse is associated with alteration of sphingosine-1-phosphate/Rho-kinase signalling pathway in human vaginal wall

Abstract

Pelvic organ prolapse (POP) is a debilitating condition of unknown aetiology affecting > 50% of women over 40 years of age. In POP patients, the vaginal walls are weakened allowing descent of pelvic organs through the vagina. We sought to determine if sphingosine-1-phosphate (S1P) signalling, which regulates smooth muscle contractility and apoptosis via the RhoA/Rho-kinase (ROK) pathway, is altered in the vagina of women with POP. Utilising anterior vaginal wall specimens, we provide novel demonstration of the S1P pathway in this organ. Additionally, comparing specimens from women having pelvic reconstructive surgery for POP and control subjects, we reveal increases in mRNA expression of the three major mammalian S1P receptors (S1P1-S1P3), and RhoA and the ROK isoforms: ROKα and ROKβ in POP patients, which correlates with a decrease in elastic fibre assembly pathway constituents. Taken together, our data suggest the S1P/ROK pathway as a novel area for future POP research and potential therapeutic development.

Hydronephrosis and utero-vaginal prolapse in postmenopausal women: management and treatment

“…As a result these patients experience a low quality of life (QoL). In POP patients, the vaginal walls are weakened allowing descent of pelvic organs (7,8). Bladder, uterus and rectum first come down into vagina and after protrude out of hymen.…”

Genome‑wide DNA methylation analysis of uterosacral ligaments in women with pelvic organ prolapse

“…Integrins interact with the ECM to generate large molecular complexes by focal adhesions. The study of Rhee et al (38) revealed that POP is associated with alterations in the sphingosine-1-phosphate/Rho-kinase signaling pathway, which could be reduced by a Rho-kinase inhibitor. Apart from ITGAV, there were two other genes, which were hypermethylated, ITGA9 and ITGB5, which require further investigation.…”

Deletion of RhoA in Progesterone Receptor–Expressing Cells Leads to Luteal Insufficiency and Infertility in Female Mice

“…Defined in vivo functions of RhoA in the female reproductive system are largely unexplored despite implications of RhoA signaling in tissues/cells from vagina, uterus, and ovary (4–13). RhoA expression was increased in the vaginal wall of patients with pelvic organ prolapse (4).…”

“…RhoA expression was increased in the vaginal wall of patients with pelvic organ prolapse (4). Our microarray analysis revealed high levels of RhoA messenger RNA (mRNA) expression in the peri-implantation mouse uterine luminal epithelium (5).…”

“…RhoA has critical cellular functions (1–3) and has been widely detected in the female reproductive system (4–13), but its in vivo functions in female reproduction have not been established. Therefore, it was hypothesized that RhoA played critical roles in female reproduction.…”