Mechanosensitive Vaginal Epithelial Adenosine Triphosphate Release and Pannexin 1 Channels in Healthy, in Type 1 Diabetic, and in Surgically Castrated Female Mice

Background: Distension of hollow organs is known to release adenosine triphosphate (ATP) from the lining epithelium, which triggers local responses and activates sensory nerves to convey information to the central nervous system. However, little is known regarding participation of ATP and mediators of ATP release, such as Pannexin 1 (Panxl) channels, in mechanisms of vaginal mechanosensory transduction and of changes imposed by diabetes and menopause, conditions associated with vaginal dysfunction and risk for impaired genital arousal. Aim: To investigate if intravaginal mechanical stimulation triggers vaginal ATP release and if (a) this response involves Panxl channels and (b) this response is altered in animal models of diabetes and menopause. Methods: Diabetic Akita female mice were used as a type 1 diabetes (T1D) model and surgical castration (ovariectomy [OVX]) as a menopause model. Panxl-null mice were used to evaluate Panxl participation in mechanosensitive vaginal ATP release. Vaginal washes were collected from anesthetized mice at baseline (nonstimulated) and at 5 minutes after intravaginal stimulation. For the OVX and Sham groups, samples were collected before surgery and at 4, 12, 22, 24, and 28 weeks after surgery. ATP levels in vaginal washes were measured using the luciferin-luciferase assay. Panxl mRNA levels in vaginal epithelium were quantified by quantitative polymerase chain reaction. Outcomes: The main outcome measures are quantification of mechanosensitive vaginal ATP release and evaluation of impact of Panxl deletion, OVX, and T1D on this response. Results: Intravaginal mechanical stimulation induced vaginal ATP release was 84% lower in Panx1-null (P <.001) and 76% lower in diabetic (P <.0001) mice compared with controls and was reduced in a progressive and significant manner in OVX mice when compared with Sham. Panxl mRNA expression in vaginal epithelium was 44% lower in diabetics than that in controls (P <.05) and 40% lower in OVX than that in the Sham (P <.05) group. Clinical Translation: Panxl downregulation and consequent attenuation of mechanosensitive vaginal responses may be implicated in mechanisms of female genital arousal disorder, thereby providing potential targets for novel therapies to manage this condition. Strengths & Limitations: Using animal models, we demonstrated Panxl involvement in mechanosensitive vaginal ATP release and effects of T1D and menopause on this response and on Panxl expression. A limitation is that sex steroid hormone levels were not measured, precluding correlations and insights into mechanisms that may regulate Panxl expression in the vaginal epithelium. Conclusions: Panxl channel is a component of the vaginal epithelial mechanosensory transduction system that is essential for proper vaginal response to mechanical stimulation and is targeted in T1D and menopause. Copyright (C) 2020, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.