Identification of temporal and spatial changes in myometrial gene expression during parturition may further the understanding of the coordinated regulation of myometrial contractions during parturition. The objective of this study was to compare the gene expression profiles of human fundal myometrium from pregnant women before and after the onset of labor using a functional genomics approach, and to further characterize the spatial and temporal expression patterns of three genes believed to be important in parturition. Fundal myometrial mRNA was isolated from five women in labor and five women not in labor, and analyzed using human UniGEM-V microarrays with 9182 cDNA elements. Real-time polymerase chain reaction using myometrial RNA from pregnant women in labor or not in labor was used to examine mRNA levels for three of the genes; namely, prostaglandin-endoperoxide synthase 2 (PTGS2), calgranulin B (S100A9), and oxytocin receptor (OXTR). The spatial expression pattern of these genes throughout the pregnant uterus before and after labor was also determined. Immunolocalization of cyclooxygenase-2 (also known as PTGS2) and S100A9 within the uterine cervix and myometrium were analyzed by immunohistochemistry. Few genes were differentially expressed in fundal myometrial tissues at term with the onset of labor. However, there appears to be a subset of genes important in the parturition cascade. The cellular properties of S100A9, its spatial localization, and dramatic increase in cervix and myometrium of women in labor suggest that this protein may be very important in the initiation or propagation of human labor.

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Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3 Pelvic organ prolapse is a common pelvic floor disorder with substantial financial, social, and psychological implications.1-3 More than 11% of women will ultimately require surgical correction of prolapse or incontinence in their lifetimes. 4 Despite the prevalence of prolapse, the true pathophysiology of the disease is not well understood although epidemiological studies indicate that aging and vaginal parity are major risk factors.

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-

In this preclinical animal model, direct, but not intravenous, injection of MSCs into the injured anal sphincter at the time of repair resulted in improved contractile function of the sphincter after injury, increased matrix deposition in the external anal sphincter, and increased expression of TFG-β1 and lysyl oxidase in the acute phase after injury.

In this animal model, injection of myogenic stem cells at the time of external anal sphincter repair resulted in enhanced contractile function at 90 days compared with repair alone. Without repair, function of the external anal sphincter was not improved by stem cell therapy at any time point. These results suggest that addition of myogenic stem cells improves both acute and long-term function of the external anal sphincter after mechanical injury.

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.

Background:The function of fetal fibronectin (fFN) in the pathogenesis of preterm labor is not known. Results: fFN activates MMP-1, MMP-9, and COX-2 in mesenchymal cells and causes preterm labor in mice. Conclusion: fFN is biologically active and plays a significant role in the pathogenesis of preterm labor. Significance: Signaling of fFN in fetal membranes is important in the pathophysiology of premature preterm rupture of the membranes.