Cellular mechanisms in the vagina of women with recurrent vaginal prolapse after prolapse surgery

Pelvic organ prolapse (POP) is a debilitating condition characterized by the downward movement of the vaginal and/or the uterus and bladder through the vaginal opening. POP incidence is 40% in women between the ages of 50-79 years.1,2 Despite this high incidence, its underlying pathophysiology is still not entirely understood.3 Surgery is the main treatment option, but up to 29% of treated patients experience recurrence of vaginal prolapse.1,4 The anterior vaginal wall is not only the most likely site of POP, but also the most likely location for prolapse recurrence after prolapse surgery.5-7 Recurrent vaginal prolapse is treated with more surgery that has even higher rates of recurrence. There is a clear need for preventative and non-surgical strategies for women who are at risk of undergoing repetitive surgeries for recurrent vaginal prolapse. However, our ability to develop effective, novel treatments is hindered by the lack of understanding of the altered tissue micro-environment and cellular function in the human POP vagina after prolapse surgery. This proposal addresses this knowledge gap. The primary components of the vagina are fibroblasts, smooth muscle cells (SMCs), and connective tissue. The reciprocal interplay between these components within the vaginal microenvironment is integral to vaginal function.8 Histological and biochemical alterations in the vagina of women with POP have been widely documented showing decreased SMCs, altered contractile function,9,10 and connective tissue deficiencies.11,12 The central hypothesis of this project is that POP surgery induces changes in the connective tissue of the POP vagina in conjunction with changes in fibroblast function and SMC loss. This leads to deficient vaginal properties that render the vagina susceptible to recurrent prolapse. This hypothesis will be tested by pursing two specific aims: 1) Examine the effect of POP surgery on the human vagina; and 2) Investigate altered vaginal fibroblast function in recurrent vaginal prolapse after POP surgery. In the first aim, vaginal wall tissues obtained from postmenopausal women undergoing primary POP surgery (controls) will be compared to those of age-matched women undergoing repeat POP surgery for recurrent vaginal prolapse (cases) through tissue biomechanical testing, histology, and gene/protein assays. For the second aim, in vitro studies of case and control fibroblasts will be conducted to examine cellular gene/protein expression, the proteins secreted by fibroblasts during culture, and fibroblast function in response to TGF-1 (a cytokine involved in wound healing). The proposed research is innovative in its establishment of foundational knowledge on the microenvironment and cellular pathways and functions in the recurrent prolapsed vagina after primary POP surgery. The proposed research is significant because unless we have data on this new vaginal landscape, we cannot generate hypotheses to address the high failure rates of repeat POP surgeries. The results of this research will set the stage for development of effective treatments to address recurrent vaginal prolapse. Project Number: 1R21HD118330-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: BERTHA CHEN | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $423,500 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 EMS-V (59)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11833001