Deletion of cGAS Preserves Vaginal Tissue Mechanics in a Mouse Model of Prolapse

Objectives: The etiology of pelvic organ prolapse (POP) is multifactorial and poorly understood. The process of cellular senescence is a likely contributor, specifically the Cyclic GMP-AMP Synthase (cGAS) cytosolic DNA sensor. Deletion of this gene in Fibulin-5 knockout mice (DKO) has been shown to rescue the POP phenotype, but the effect of this deletion on tissue strength and functionality remains unknown. The objective of this study is to compare vaginal distensibility and stiffness of the DKO vaginal tissue with WT controls.

Methods: WT and DKO female mice (n=3/genotype) at 6 months of age were used in this IACUC-approved study. Prior to sacrifice, MOPQ measurements were taken. The vagina was explanted and cannulated onto an extension-inflation device (Fig 1). To ensure that measurements are consistent and repeatable, the tissue was preconditioned before vaginal function was evaluated by cyclic loading. Material stiffness, a measure of how tissues resist changes in shape during loading, was quantified by taking the slope of the stress-stretch curve within a physiologic pressure range determined from our prior work. Unpaired t-tests were used for statistical analysis with significance at p< 0.05.

Results: No statistically significant differences were identified in perineal body length (Fig 2A) or perineal bulge (Fig 2B) between the WT and DKO. Biomechanical results showed a slight decrease in distensibility in the DKO vagina compared to the WT control (Fig 2C). No statistically significant differences were found between the WT and DKO material stiffness.

Conclusions: In this study, we found no statistically significant differences in MOPQ measurements or vaginal strength between DKO and WT. These findings provide further evidence that deletion of cGAS in a murine model of POP results in POP rescue without deleterious effects in vaginal function and biomechanical integrity. Future studies will need to compare additional time points, as well as to compare the DKO mechanics to the Fibulin-5 knockout.