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Pelvic organ prolapse is strongly associated with a history of vaginal delivery. The mechanisms by which pregnancy and parturition lead to failure of pelvic organ support, however, are not known. Recently, it was reported that mice with null mutations in lysyl oxidase-like 1 (LOXL1) develop pelvic organ prolapse. Elastin is a substrate for lysyl oxidase (LOX) and LOXL1, and LOXL1 interacts with fibulin-5 (FBLN5). Therefore, to clarify the potential role of elastic fiber assembly in the pathogenesis of pelvic organ prolapse, pelvic organ support was characterized in Fbln5 ؊/؊ mice, and changes in elastic fiber homeostasis in the mouse vagina during pregnancy and parturition were determined. Pelvic organ prolapse in Pelvic organ prolapse is a common condition that negatively impacts the quality of life of millions of women.1 In one study, 11% of women had surgery for urinary incontinence or pelvic organ prolapse during their lifetime.1 For hundreds of years, it has been recognized that the process of pregnancy, labor, and delivery is associated with the development of prolapse.2,3 In addition to vaginal birth, epidemiological studies suggest that aging is also a significant risk factor for developing pelvic organ prolapse. The mechanisms by which pregnancy, parturition, and aging lead to failure of pelvic organ support, however, are not known. Furthermore, the mechanisms that mediate the delayed manifestations of childbirth-associated injuries of the pelvic floor during childbirth are not understood.Support of the pelvic viscera is maintained by fibromuscular connective tissues of the female pelvic floor and a group of skeletal muscles known as the levator ani. It is believed that the levator ani can sustain direct or neurological damage during childbirth and other neuropathic processes. Even so, defects in the levator ani (or even the reduced ability of the levator to contract) do not correlate with pelvic organ prolapse in many women. 4 -7 Thus, a potential role of fibromuscular connective tissue in the pathophysiology of pelvic organ prolapse has been proposed by us 8,9 and others. 10 The supportive connective tissues of the vagina, although essentially a continuous sheet, are generally subdivided into three levels of support: the uterosacral and cardinal ligaments (level I), paravaginal connective tissues suspending the lateral vaginal walls to the arcus tendineous and fascia of the levator ani (level II), and the perineal membrane and perineal body (level III).11 Studies conducted in the vaginal wall of women with pelvic organ prolapse reveal marked abnormalities in histomorphology, 8,12 biochemistry, 9 gene expression, 13 and ultrastructural morpholo-

Recent evidence indicates that failure of elastic fiber assembly and synthesis is involved in the pathophysiology of pelvic organ prolapse in mice. It has been long been hypothesized that parturition-induced activation of proteases in the vaginal wall and its supportive tissues may contribute to pelvic organ prolapse in women. In this investigation, we determined the expression of matrix metalloproteases with elastase activity (matrix metalloproteinase [MMP] 2, MMP9, and MMP12) and their inhibitors in the vaginal wall of nonpregnant, pregnant, and postpartum mice. Data obtained using mRNA levels and enzyme activity measurements indicate that MMP2, MMP9, and 21- to 24-kDa caseinolytic serine proteases are regulated in vaginal tissues from pregnant and postpartum mice. Although suppressed during pregnancy and the early postpartum time period, MMP2 and MMP9 enzyme activities are increased after 48 h, a time when mRNA levels of protease inhibitors (tissue inhibitor of MMP2 [Timp2], cystatin C [Cst3], and alpha-1 antitrypsin [Serpina1]) are decreased. We conclude that recovery of the vaginal wall from pregnancy and parturition requires increased elastic fiber assembly and synthesis to counteract the marked increase in elastolytic activity of the postpartum vagina.

Two mouse models of pelvic organ prolapse have been generated recently, both of which have null mutations in genes involved in elastic fiber synthesis and assembly (fibulin 5 and lysyl oxidase-like 1). Interestingly, although these mice exhibit elastinopathies early in life, pelvic organ prolapse does not develop until later in life. In this investigation we developed and validated a tool to quantify the severity of pelvic organ prolapse in mice, and we used this tool prospectively to study the role of fibulin 5, aging, and vaginal proteases in the development of pelvic organ prolapse. The results indicate that >90% of Fbln5(-/-) mice develop prolapse by 6 mo of age, even in the absence of vaginal delivery, and that increased vaginal protease activity precedes the development of prolapse.

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