Suppression of Ephx2 in endothelial cells of penile cavernouse tissue improves SHR erectile function

Abstract Introduction Hypertension is a major cause of erectile dysfunction (ED). The impact of hypertension on the transcriptome and proteome of penile corpus cavernosum tissue, as well as its relationship with erectile dysfunction, is not clear. This study aimed to explore the differential expression of genes and proteins in the penile corpus cavernosum of spontaneously hypertensive rats (SHRs) and its relationship with erectile function. Methods Transcriptome and proteome sequencing of the penile corpus cavernosum in Wistar–Kyoto (WKY) rats and SHRs was performed to identify key genes and proteins whose expression significantly changed and whose expression was associated with that of the eNOS pathway. SHRs were injected with adeno-associated virus carrying siRNA targeting Ephx2 or treated with icariin. Western blot, qPCR, and immunohistochemistry were used to validate Ephx2 expression and AKT/eNOS pathway activation. Erectile function was assessed by the ratio of ICPmax/MAP. Results Ephx2 was expressed in the cytoplasm of rat penile corpus cavernosum endothelial cells. Compared with those in WKY rats, the expression of Ephx2 in the penile corpus cavernosum endothelial cells in SHRs was significantly greater, whereas the p-AKT/AKT, p-eNOS/eNOS, and ICPmax/MAP ratios were markedly lower (P < 0.05). In the SHR group transfected with an AAV vector carrying siRNA targeting Ephx2 and the SHR group treated with icariin, Ephx2 expression in penile corpus cavernosum endothelial cells was significantly lower than that in the SHR group, whereas the p-AKT/AKT, p-eNOS/eNOS, and ICPmax/MAP ratios were significantly greater than in the SHR group (P < 0.05). Conclusions The significant upregulation of Ephx2 expression in SHR penile corpus cavernosum endothelial cells inhibited the AKT/eNOS pathway, leading to ED. Both adeno-associated viral vectors carrying siRNA targeting Ephx2 and icariin can suppress Ephx2 expression in the penile corpus cavernosum endothelial cells of SHRs. Further activation of the AKT/eNOS pathway improves endothelial function, resulting in enhanced erectile function in SHRs. Inhibiting Ephx2 expression in penile cavernous endothelial cells may represent a potential therapeutic approach for hypertension-induced ED.