A low androgen state impairs erectile function by suppressing EPAC1 in rat penile corpus cavernosum

Background: Exchange proteins activated by cAMP 1 (EPAC1) can promote vasodilatation by regulating endothelial nitric oxide synthase (eNOS) activity through the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway and prevent vascular smooth muscle contraction by restraining the ras homolog gene family, member A/Rho-associated coiled-coil forming protein kinase (RhoA/ROCK) pathway. However, the relationship among EPAC1, androgen and erectile function is still unknown. Therefore, we attempted to investigate whether EPAC1 expresses in penile corpus cavernosum of rats and how EPAC1 affects erectile function under low androgenic conditions.

Methods: Thirty 8-week-old Sprague-Dawley male rats were randomly divided into six groups (n=5): sham operation (sham), castrated, castrated + testosterone replacement (castrated + T), sham + EPAC1 over-expression lentivirus (sham + EPAC1), castrated + empty lentivirus vector (castrated + empty vector), and castrated + EPAC1. Four weeks after the operation, the lentivirus vectors carrying the EPAC1 gene were injected into the penile corpus cavernosum of the sham + EPAC1 and castrated + EPAC1 groups (1×10⁸ TU/mL, 20 µL per rat). A week after injection, the ratio of maximum intracavernous pressure to mean arterial pressure (ICPmax/MAP) and the levels of serum testosterone (T), nitric oxide (NO), the active form of RhoA (RhoA-GTP), AKT, phospho-AKT (p-AKT), eNOS, phospho-eNOS (p-eNOS), p-AKT/AKT, p-eNOS/eNOS and EPAC1 levels were measured.

Results: In comparison to the sham group, ICPmax/MAP and EPAC1 content in the castrated group were significantly reduced. EPAC1 is primarily located in the cyto-membrane and cytoplasm of endothelial cells and smooth muscle cells in the rat penile corpus cavernosum. In comparison to the sham group, the T, ICPmax/MAP and NO levels of the castrated group were significantly reduced (P<0.01). Meanwhile, the RhoA-GTP concentration in the castrated + EPAC1 group was reduced in comparison with the castrated + empty vector group (P<0.01). Compared with the castrated + empty vector group, the p-AKT/AKT, EPAC1 and p-eNOS/eNOS levels in the castrated + EPAC1 group were significantly increased (P<0.05).

Conclusions: Androgen deficiency can suppress EPAC1 expression in the penile corpus cavernosum of rats, while the up-regulation of which can improve the erectile function of castrated rats.