Endothelin-1 and diabetes mellitus-induced erectile dysfunction: from pathogenesis to therapeutic potential

Diabetes mellitus-induced erectile dysfunction (DMED) is a common complication of diabetes. In recent years, clinical and experimental studies have demonstrated the crucial role of vascular endothelial structure and function damage in the pathogenesis of DMED, suggesting the core role of vascular lesions in DMED. Endothelin-1 (ET-1) is currently reported as a potent long-acting vasoconstrictor, which could be upregulated by hyperglycemia and is considered as a biomarkerof diabetic endothelial dysfunction. In this study, we review the increase of ET-1 level in a hyperglycemic environment and the mechanisms by which it contributes to the pathogenesis of DMED. Clinical and experimental evidence demonstrate that hyperglycemia significantly upregulates ET-1 levels, which could arise from the specific signaling pathway or epigenetic changes such as DNA hypomethylation. Prolonged ET-1 elevation could lead to inflammation, oxidative stress, and reduced nitric oxide (NO) generation and utilization rate, which induce the occurrence of penile erectile dysfunction. Furthermore, we explore the therapeutic potential of regulating ET-1 expression for DMED treatment, by interventions targeting ET-1 synthesis or receptor blockade. In a word, our study summarized that DMED could be driven by ET-1 dysregulation, offering new insights for future clinical trials to improve the treatment of DMED and other diabetic complications.