Hypertension impairs erectile function in spontaneously hypertensive rats by suppressing adiponectin in the penile...

Hypertension is a well-established risk factor for erectile dysfunction and is closely associated with endothelial dysfunction and reduced nitric oxide bioavailability; however, the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether hypertension impairs erectile function by regulating adiponectin (APN) expression and the phosphoinositide 3-kinase/protein kinase B/endothelial nitric oxide synthase (PI3K/AKT/eNOS) signaling pathway in the penile corpus cavernosum and to explore whether APN-related PI3K/AKT/eNOS signaling may be involved in the beneficial effects of icariin (ICA) in spontaneously hypertensive rats (SHRs).

Twelve-week-old Wistar-Kyoto (WKY) rats and SHRs were randomly assigned to six groups (n=6 per group) as follows: WKY, WKY + ICA, SHR, SHR + ICA, SHR + negative control (SHR + NC), and SHR + adeno-associated virus (SHR + AAV). Rats in the SHR + AAV group received an intracavernosal injection of an AAV vector carrying the APN gene (10 µL/rat, 4.31×10¹³ vg/mL). The rats in the SHR + ICA group received ICA (10 mg/kg/day) by gavage for four weeks. Intracavernosal AAV injection was performed at week 3, followed by a two-week expression period. Erectile function was evaluated using the ratio of maximal intracavernous pressure (ICPmax) to mean arterial pressure (MAP), and serum testosterone (T) levels were measured after the AAV expression period. The protein expression levels of APN, phosphorylated PI3K (p-PI3K), PI3K, AKT, phosphorylated AKT (p-AKT), eNOS, and phosphorylated eNOS (p-eNOS), as well as nitric oxide (NO) content, were assessed in the penile corpus cavernosum.

The NO levels in the penile corpus cavernosum and the ICPmax/MAP ratio were significantly lower in SHRs than in WKY rats. APN expression was markedly reduced in endothelial cells of the penile corpus cavernosum in SHRs, and the p-PI3K/PI3K, p-AKT/AKT, and p-eNOS/eNOS ratios in the penile corpus cavernosum were also significantly lower in SHRs than in WKY rats. Compared with the SHR group, both ICA treatment (SHR + ICA) and AAV-mediated APN overexpression (SHR + AAV) significantly increased NO production and the ICPmax/MAP ratio (P<0.05), accompanied by increased APN expression and enhanced phosphorylation of PI3K, AKT, and eNOS in the penile corpus cavernosum (P<0.05).

Hypertension induces erectile dysfunction (ED) partly by downregulating APN expression in endothelial cells of the penile corpus cavernosum and suppressing the PI3K/AKT/eNOS signaling pathway. AAV-mediated APN overexpression upregulated APN expression, activated the PI3K/AKT/eNOS pathway, and improved erectile function in SHRs, whereas ICA treatment improved erectile function and may increase APN expression and enhance PI3K/AKT/eNOS signaling.