Elastic Fiber Homeostasis in the Vaginal Wall

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DESCRIPTION (provided by applicant): Pelvic floor disorders affect up to one-third of adult women. One of the most prevalent pelvic floor disorders is pelvic organ prolapse, a condition in which the pelvic organs (bladder, vagina, cervix and uterus) herniate through the vaginal opening. Up to 11% of women have surgery for pelvic organ prolapse or urinary incontinence in their lifetime and more than 225,000 inpatient surgical procedures for pelvic organ prolapse are performed per year in the United States at an estimated annual direct medical cost of over one billion dollars. Although multiple mechanisms have been hypothesized to contribute to the development of pelvic organ prolapse, none fully explain the origin and natural history of this process. Epidemiologic studies indicate that vaginal birth and aging are the two major risk factors for developing pelvic organ prolapse. The specific effects of pregnancy and parturition and aging on pelvic floor support mechanisms have not been identified. Recently, it was reported that mice with null mutations in the gene encoding lysyl oxidase like 1 (LOXL1) develop pelvic organ prolapse. We discovered that fibulin-5 (FblnS) knockout mice also develop severe urogenital prolapse. Interestingly, LOXL1 and fibulin-5 are proteins involved in synthesis and assembly of elastic fibers into the extracellular matrix, and both mouse models develop severe prolapse of the vaginal wall after giving birth. By way of preliminary studies, we find that transcripts of two enzymes that degrade elastin are increased significantly in the vaginal muscularis of women with pelvic organ prolapse. These findings, together with results from these two animal models, provide the foundation of the overall hypothesis of this grant application, namely that pelvic organ support is maintained by a delicate balance between the synthesis/assembly and degradation of elastic fibers in the vaginal wall. We propose that damage to the elastic tissue of the vagina and its supporting structures leads to loss of vaginal support. The degree of functional loss depends on the extent of initial injury, presence of natural protease inhibitors that modulate enzymatic damage, and the ability of elastin fibers to undergo repair. In this application, we propose (1) to determine the regulation of elastic fiber homeostasis in the vagina and supportive connective tissues of the pelvic floor during pregnancy, parturition, and the postpartum time period; (2) To determine the impact of steroid hormones and mechanical trauma on pelvic organ prolapse and elastic fiber formation and degradation; and (3) to test the hypothesis that postpartum synthesis of fibulin-5 is crucial for recovery of the vaginal wall from vaginal childbirth.