Optimizing Minoxidil Delivery for Persistent Elastin Deposition in the Murine Vaginal Wall

Pelvic organ prolapse (POP) is an abnormal descent of the female pelvic organs that protrudes to, or through, the vaginal canal. Prolapse is caused by a loss of structural integrity of the pelvic organs and their connective tissue support and coincides with a reduction in vaginal elastic fibers either through enzymatic (as with age) or mechanical (as with vaginal delivery) disruption and fragmentation. One-in-eight women (13%) will require a surgical intervention to restore normal pelvic anatomy during their lifetime and over one-third of these procedures (38%) will fail or induce complications due to either insufficient native tissue strength or biomechanical mismatches in graft and adjacent tissue properties. The development of new and effective therapies for improving prolapse surgery outcomes is slow and the FDA mandate to stop selling and distributing transvaginal meshes underscores the need to study and develop innovative solutions. Currently, prolapse is treated surgically and there are no viable pharmaceutical treatment options focused on targeting the underlying cellular and molecular consequences of POP onset and progression in connective tissues. Towards this end, we propose a first-of-its-kind biologically motivated treatment that seeks to facilitate de novo vaginal elastogenesis. Motivated by prior findings of its use in the cardiovascular system, the goal of this work is to optimize the local administration of minoxidil, a promising ATP-dependent potassium channel opener, to the vaginal wall as a biologic therapeutic to improve pelvic floor function and integrity in mice. Our preliminary data shows that minoxidil treatment increased tropoelastin gene expression by primary murine vaginal cells and upregulated elastin protein secretion (soluble in media) and deposition (insoluble in tissue) in cultured vaginal explants. Finally, daily in vivo administration of minoxidil via local injections in the posterior vaginal wall led to an ~50% increase in elastic fiber area in the wall after seven days. To date, we have only explored a single concentration and delivery method for vaginal minoxidil treatment. Thus, we hypothesize that systematic investigation of dosage, delivery method, and treatment duration has the potential to optimize the in vivo elastogenic effects of vaginal minoxidil treatment. In this proposal, we will use biomechanical and biochemical assays to investigate the ability of increasing concentrations of local minoxidil injections to alter vaginal elastin production in female CD-1 mice of varying ages and parity status (Aim 1) and explore the efficiency of three separate routes of in vivo minoxidil delivery (local injection, local thermosensitive hydrogel, and systemic oral) on vaginal elastic fiber synthesis (Aim 2). Finally, we will explore the potential for minoxidil to promote elastic fiber persistence in the vaginal wall after treatment cessation (Aim 3). Outcomes from this work will demonstrate the therapeutic potential for minoxidil to generate vaginal elastic fibers in vivo, thereby improving biomechanical stability of the vaginal wall. We expect these results to have an important positive impact on women’s health and the management of pelvic floor disorders by yielding the first non-invasive biologic treatment to prevent or halt the progression of prolapse. Project Number: 1R21HD118466-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: MATTHEW BERSI | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $441,884 | Activity Code: R21 | Study Section: Kidney and Urological Systems Function and Dysfunction Study Section[KUFD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11304903