Pelvic Organ Support in Animals with Partial Loss of Fibulin-5 in the Vaginal Wall.

Kathleen Chin,T Ignacio Montoya,R Ann Word,Haolin Shi,Hiromi Yanagisawa,Cecilia Wieslander,Sunil Balgobin,Diego Fraidenraich

doi:10.1371/journal.pone.0152793

Kathleen Chin, T Ignacio Montoya + Show 6 more

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https://doi.org/10.1371/journal.pone.0152793

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Journal: PloS one	Publication Date: Apr 28, 2016
Citations: 19	License type: CC BY 4.0

Affiliation: The University of Texas Southwestern Medical Center

Abstract

Compromise of elastic fiber integrity in connective tissues of the pelvic floor is most likely acquired through aging, childbirth-associated injury, and genetic susceptibility. Mouse models of pelvic organ prolapse demonstrate systemic deficiencies in proteins that affect elastogenesis. Prolapse, however, does not occur until several months after birth and is thereby acquired with age or after parturition. To determine the impact of compromised levels of fibulin-5 (Fbln5) during adulthood on pelvic organ support after parturition and elastase-induced injury, tissue-specific conditional knockout (cKO) mice were generated in which doxycycline (dox) treatment results in deletion of Fbln5 in cells that utilize the smooth muscle α actin promoter-driven reverse tetracycline transactivator and tetracycline responsive element-Cre recombinase (i.e., Fbln5f/f/SMA++-rtTA/Cre+, cKO). Fbln5 was decreased significantly in the vagina of cKO mice compared with dox-treated wild type or controls (Fbln5f/f/SMA++-rtTA/Cre-/-). In controls, perineal body length (PBL) and bulge increased significantly after delivery but declined to baseline values within 6–8 weeks. Although overt prolapse did not occur in cKO animals, these transient increases in PBL postpartum were amplified and, unlike controls, parturition-induced increases in PBL (and bulge) did not recover to baseline but remained significantly increased for 12 wks. This lack of recovery from parturition was associated with increased MMP-9 and nondetectable levels of Fbln5 in the postpartum vagina. This predisposition to prolapse was accentuated by injection of elastase into the vaginal wall in which overt prolapse occurred in cKO animals, but rarely in controls. Taken together, our model system in which Fbln5 is conditionally knock-downed in stromal cells of the pelvic floor results in animals that undergo normal elastogenesis during development but lose Fbln5 as adults. The results indicate that vaginal fibulin-5 during development is crucial for baseline pelvic organ support and is also important for protection and recovery from parturition- and elastase-induced prolapse.

Highlights

Pelvic floor dysfunction is a prevalent disabling condition with suboptimal treatment
Overt prolapse did not occur in conditional knockout (cKO) animals, even after three pregnancies, these results suggest that Fbln5 is important for full recovery of pelvic support from vaginal delivery
Our present study showed that compromise, but not complete loss, of Fbln5 in the vaginal wall led to (i) subclinical prolapse with parturition that accumulates with increasing number of deliveries, and (ii) overt prolapse only with elastase-induced injury

Summary

Introduction

Pelvic floor dysfunction is a prevalent disabling condition with suboptimal treatment. Fbln knockout mice develop prolapse as a function of age (27% [10]) These animal models exhibit elastinopathies at birth, POP does not develop until later in life [11]. This observation suggests that abnormal elastic fibers, alone, may not be sufficient to induce prolapse, but that other factors acquired during parturition and aging, together with abnormal elastic fibers, lead to prolapse. One of these factors is likely activation of MMP-9. Elastic fiber defects alone are insufficient to activate MMP-9 because increased activity was not observed in aorta or skin from Fbln5-/- animals [14]

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