Loss of the vaginal connective tissue support results in prolapse of the pelvic viscera into the vaginal canal. Prolapse and the sequela of prolapse have a profoundly negative impact on the lives of millions of women. Eleven percent of women in the United States will undergo a major surgical procedure to repair prolapse and 30% require re-operation because of failure (4). Until now, most studies have focused on childbirth as the primary risk factor for developing prolapse; however, the majority of women do not develop prolapse until decades following childbirth indicating that other factors play a role (4-6, 35-38). In this revised grant application, we have collected a multidisciplinary team of experts to study menopause as a risk factor for prolapse by performing a comprehensive analysis of the impact of menopause on the supportive connective tissue of the vagina.
In Aims I -1 and 1-2, we propose to compare biopsies of vaginal supportive connective tissue in premenopausal and postmenopausal women not on hormone therapy to test whether a decrease in the ratios of collagen [I/(III + V)] in postmenopausal women not on hormone therapy leads to inferior biomechanical properties and predisposes to prolapse. In addition, we determine whether quantitative changes in the amount of elastin and/or smooth muscle relative to collagen correlate with a deterioration in biomechanics. Finally, in this section of the grant, we ask whether hormone therapy in postmenopausal women improves the structural and biomechanical deficiencies identified in the vaginal connective tissue of postmenopausal women not on hormone therapy.
In Aim II -1, we will investigate whether the changes in these structural components of the vaginal connective tissue are due to an alteration in the expression and activity pattern of the connective tissue degrading Matrix Metalloproteinases (MMPs) relative to their endogenous inhibitors (Tissue Inhibitors of MMPs, TIMPs). We measure the expression and activity of individual metalloproteinases using biochemical assays and net proteolytic activity in tissue using substrate degradation assays. The mechanism of regulation of MMP/TIMP expression by 17-beta-estradiol +/- progesterone is studied, in parallel, in cells derived from the supportive vaginal connective tissue in culture. Because of the limitations inherent in studies on human tissues, we use a rat model in Aims III-1 and 111-2, to determine whether supplementation with 17-beta-estradiol, 17-beta-estradiol and progesterone or the MMP inhibitor - chemically modified tetracycline-8, prevents the deterioration in the biomechanical properties of the vaginal connective tissue that occur following a surgically induced menopause in middle aged rats. We have exciting preliminary data to support each of the Aims outlined in the study. We believe that the results of this revised grant proposal will elucidate an important mechanism that predisposes women to vaginal wall prolapse and will ultimately contribute to the development of preventative strategies to treat this common and debilitating, yet vastly understudied disease.
| Easley, Deanna C; Abramowitch, Steven D; Moalli, Pamela A (2017) Female pelvic floor biomechanics: bridging the gap. Curr Opin Urol 27:262-267 |
| Barone, William R; Amini, Rouzbeh; Maiti, Spandan et al. (2015) The impact of boundary conditions on surface curvature of polypropylene mesh in response to uniaxial loading. J Biomech 48:1566-74 |
| Brown, Bryan N; Mani, Deepa; Nolfi, Alexis L et al. (2015) Characterization of the host inflammatory response following implantation of prolapse mesh in rhesus macaque. Am J Obstet Gynecol 213:668.e1-10 |
| Skoczylas, Laura C; Jallah, Zegbeh; Sugino, Yoshio et al. (2013) Regional differences in rat vaginal smooth muscle contractility and morphology. Reprod Sci 20:382-90 |
| Feola, Andrew; Duerr, Robert; Moalli, Pamela et al. (2013) Changes in the rheological behavior of the vagina in women with pelvic organ prolapse. Int Urogynecol J 24:1221-7 |
| Feola, Andrew; Moalli, Pamela; Alperin, Marianna et al. (2011) Impact of pregnancy and vaginal delivery on the passive and active mechanics of the rat vagina. Ann Biomed Eng 39:549-58 |
| Alperin, Marianna; Feola, Andrew; Meyn, Leslie et al. (2010) Collagen scaffold: a treatment for simulated maternal birth injury in the rat model. Am J Obstet Gynecol 202:589.e1-8 |
| Zong, Wenjun; Stein, Suzan E; Starcher, Barry et al. (2010) Alteration of vaginal elastin metabolism in women with pelvic organ prolapse. Obstet Gynecol 115:953-61 |
| Zong, Wenjun; Jallah, Zegbeh C; Stein, Suzan E et al. (2010) Repetitive mechanical stretch increases extracellular collagenase activity in vaginal fibroblasts. Female Pelvic Med Reconstr Surg 16:257-262 |
| Jones, Keisha A; Feola, Andrew; Meyn, Leslie et al. (2009) Tensile properties of commonly used prolapse meshes. Int Urogynecol J Pelvic Floor Dysfunct 20:847-53 |
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