Pelvic organ prolapse (POP) affects 50% of women, is characterized by the descent of pelvic organs into the vagina, and is associated with age and childbirth. Birth injuries can damage DNA in vaginal cells, activating cGAS, a DNA sensor that triggers immune responses. Prolonged cGAS activation promotes inflammation, weakening pelvic tissues, particularly fibulin-5, which forms elastic fibers critical for pelvic stability. This study investigated if knocking out both the cGAS and fibulin-5 genes in mice (DKO) restores vaginal function. Vaginal modulus was quantified using biaxial inflation testing in POP mice with fibulin-5 knocked out (F5KO) and DKO, compared to wildtype controls (WT).
 
15 nulliparous female mice (4-6 months old) were divided by genotype: WT, F5KO, and DKO (UTSW IACUC approved). Vaginas were mounted onto a biaxial inflation device to quantify tissue modulus at physiologic loading conditions.

The F5KO was less distensible than the WT and DKO as shown by a stress-strech curve. Circumferential modulus significantly increased in the F5KO compared to WT(p=0.002, p=0.04) and DKO(p=0.003, p=0.05), but DKO was not significantly different from WT controls. 

This study showed that deleting cGAS restored the biomechanical functions of the murine vagina. F5KO mice exhibited significant mechanical differences compared to WT and DKO mice, regardless of prolapse grade. The DKO did not show any significant differences in vaginal biomechanical properties from the WT. Clark+ showed that vaginal distensibility in F5KO mice decreased with grade 1 POP but increased with grades 2-3 compared to WT mice. Zheng+ also identified cGAS as a key mediator in age-related diseases, regulating cellular dysfunction and inflammation. Taken together, these findings suggest that targeting the cGAS pathway may mitigate the negative effects of Fibulin-5 deficiency and offer a promising therapeutic approach to preserve tissue strength and improve pelvic health.