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Abstract Introduction Diabetes mellitus (DM), a primary cause of erectile dysfunction (ED), is a pancreatic β-cell dysfunction that leads to insulin deficiency and resistance, resulting in microvascular complications. Argonaute 2 (Ago2), a catalytic engine in mammalian RNA interference, is involved in neurovascular regeneration under inflammatory conditions. Objective In the present study, we aimed to determine whether an exogenous injection of Ago2 proteins can improve erectile function in STZ-induced type-1 diabetic mice and explore the specific mechanisms of Ago2 in the process. Methods Eight-week-old male C57BL/6 mice were used for in vivo study. The detailed mechanisms were evaluated in age-matched control or STZ-induced type-1 diabetic mice. Mouse cavernous endothelial cells and human umbilical vein endothelial cells were used for in vitro study. The function of Ago2 in high-glucose condition was evaluated by tube formation assay, migration assay, immunofluorescence stain and western blot experiments. Results We report that Ago2 administration can effectively improve penile erection by enhancing cavernous endothelial cell angiogenesis and survival under diabetic conditions. We found that although Ago2 is highly expressed around blood vessels and nerves, it is significantly reduced in the penis tissue of diabetic mice. Exogenous administration of the Ago2 protein restored erectile function in diabetic mice by reducing reactive oxygen species production-signaling pathways (inducing eNOS Ser1177/NF-κB Ser536 signaling) and improving cavernous endothelial angiogenesis, migration, and cell survival. Our study provides new evidence that Ago2 mediation may be a promising therapeutic strategy and a new approach for diabetic ED treatment. Conclusions Our study provides new insights into Ago2 function and may represent a new therapeutic approach for ED and other vascular and neurological diseases. Disclosure No.
Yin et al. (Fri,) studied this question.