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

PROJECT SUMMARY
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.

Grant Number: 1R21HD118330-01
NIH Institute/Center: NIH
Principal Investigator: BERTHA CHEN