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BACKGROUND: Erectile dysfunction (ED), defined as the inability to achieve or maintain a penile erection sufficient to satisfy sexual behavior, is prevalent worldwide. AIM: Using previous research, bioinformatics, and experimental confirmation, we aimed to discover genes that contribute to ED through regulating hypoxia in corpus cavernosum smooth muscle cells (CCSMCs). METHODS: We used the Gene Expression Omnibus to acquire the sequencing data of the corpus cavernosum transcriptome for diabetic ED and nerve injury type ED rats. We intersected the common differentially expressed genes. Further verification was performed using single cell sequencing. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate whether the differentially expressed genes are found in the corpus cavernosum. We used induced hypoxia to assess cell viability changes, and we developed a lentivirus overexpressing Cldn4 for in vitro and in vivo experiments to measure changes in JNK signaling, fibrosis, hypoxia, and erectile function. OUTCOMES: Our results indicate that targeting the JNK pathway and decreasing local hypoxia may be better options for therapeutic intervention to improve erectile function. RESULTS: We identified Cldn4 and found its expression increased in the corpora cavernosa of the 2 datasets. In addition, we found that hypoxia can increase the expression of Cldn4, activate the JNK signaling pathway, and exacerbate fibrosis in CCSMCs. Cldn4 overexpression in CCSMCs activated the JNK signaling pathway and increased fibrotic protein expression. Last, rat corpus cavernosum overexpressing Cldn4 activated the JNK signaling pathway, increased local fibrosis, and impaired erectile function. CLINICAL IMPLICATIONS: Through bioinformatics and in vitro and in vivo experiments, we found that Cldn4 has a negative effect on ED, and targeting Cldn4 may provide new ideas for ED treatment. STRENGTHS AND LIMITATIONS: Although we have identified Cldn4 as a potential target for ED treatment, we have only conducted preliminary validation on CCMSCs, and we still need to further validate in other cell lines. CONCLUSION: CCSMC hypoxia leads to increased Cldn4, in both nerve injury and diabetic ED rat models, and promotes fibrosis by activating the JNK signaling pathway.
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Background: It is difficult to diagnose hypogonadism because of the lack of objective assessments of erectile dysfunction (ED), which is caused by hypogonadism. Aim: To provide a new approach for diagnosing hypogonadism, this study evaluated the efficacy of nocturnal penile tumescence and rigidity (NPTR) testing with RigiScan for patients with ED with and without hypogonadism. Methods: From June 2021 to February 2023, 133 patients with ED (62 with hypogonadism and 71 without) underwent NPTR testing at the Department of Andrology. A detailed history of all participants was obtained. All participants also underwent a physical examination, sex hormone testing, and ultrasound examination of the cavernous vessels of the penis. Outcomes: Patient characteristics, sex hormone serum levels, and RigiScan Plus data of NPTR testing of patients with ED were obtained and evaluated. Results: Between the groups, there were no significant differences in age, body mass index, or erectile function score or in the prevalence of smoking, drinking, diabetes, hypertension, and hyperlipidemia. RigiScan data revealed differences in erection episodes per night, average event rigidity, erection durations, and percentage of tumescence greater than baseline, which were significantly lower in the testosterone-deficient group than in the normal testosterone group. The average event rigidity of the tip displayed the largest area under the curve value, with a sensitivity of 67.6%, a specificity of 85.5%, and a cutoff value of 52.50. Clinical Implications: Our findings may allow appropriate patients to receive testosterone replacement therapy, which has been shown to be an effective treatment for hypogonadism. Strengths and Limitations: This is the first study of its kind to perform a comprehensive review of the association between hypogonadism and RigiScan parameters. This study was limited by its small sample size. Conclusion: RigiScan parameters of patients with ED and testosterone deficiency were significantly lower than those of patients with normal testosterone; therefore, RigiScan is useful for the differential diagnosis of patients with ED caused by hypogonadism.
