Erectile dysfunction is a complex and common complication of diabetes mellitus, which lacks an effective treatment. The repairing role of vascular endothelium is the current research hotspot of diabetic mellitus erectile dysfunction (DMED), and the activation of PI3K/AKT/eNOS pathway positively affects the repair of vascular endothelium. The herbal extract isorhamnetin has significant vasoprotective effects and has great potential in treating DMED. This study aimed to clarify whether isorhamnetin has an ameliorative effect on DMED and to investigate the modulation of the PI3K/AKT/eNOS signaling pathway by isorhamnetin to discover its potential mechanism of action. In vivo experiments were performed using a streptozotocin-induced diabetic rat model, and efficacy was assessed after 4 weeks of isorhamnetin gavage administration at 10 mg/kg or 20 mg/kg. Erectile function in rats was assessed by maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP), and changes in corpus cavernosum (CC) fibrosis, inflammation levels, oxidative stress levels, and apoptosis were assessed by molecular biology techniques. In vitro experiments using high glucose-induced corpus cavernosum endothelial cells were performed to further validate the anti-apoptotic effect of isorhamnetin and its regulation of the PI3K/AKT/eNOS pathway. The findings demonstrated that isorhamnetin enhanced erectile function, decreased collagen content, and increased smooth muscle content in the CC of diabetic rats. In addition, isorhamnetin decreased the serum levels of pro-inflammatory factors IL-6, TNF-α, and IL-1β, increased the levels of anti-inflammatory factors IL-10 and IL-4, increased the activities of SOD, GPx, and CAT as well as the levels of NO, and decreased the levels of MDA in corpus cavernosum tissues. Isorhamnetin also increased the content of CD31 in CC tissues of diabetic rats, activated the PI3K/AKT/eNOS signaling pathway, and inhibited apoptosis. In conclusion, isorhamnetin exerts a protective effect on erectile function in diabetic rats by reducing the inflammatory response, attenuating the level of oxidative stress and CC fibrosis, improving the endothelial function and inhibiting apoptosis. The mechanism underlying these effects may be linked to the activation of the PI3K/AKT/eNOS pathway.

Phosphodiesterase type 5 inhibitors (PDE5is) constitute the primary therapeutic option for treating erectile dysfunction (ED). Nevertheless, a substantial proportion of patients, approximately 30%, do not respond to PDE5i treatment. Therefore, new treatment methods are needed. In this study, we identified a pathway that contributes to male erectile function. We show that mechano-regulated YAP/TAZ signaling in smooth muscle cells (SMCs) upregulates adrenomedullin transcription, which relaxed the SMCs to maintain erection. Using single-nucleus RNA sequencing, we investigated how penile erection stretches the SMCs, inducing YAP/TAZ activity. Subsequently, we demonstrate that YAP/TAZ plays a role in erectile function and penile rehabilitation, using genetic lesions and various animal models. This mechanism relies on direct transcriptional regulation of adrenomedullin by YAP/TAZ, which in turn modulates penile smooth muscle contraction. Importantly, conventional PDE5i, which targets NO-cGMP signaling, does not promote erectile function in YAP/TAZ-deficient ED model mice. In contrast, by activating the YAP/TAZ-adrenomedullin cascade, mechanostimulation improves erectile function in PDE5i nonrespondent ED model rats and mice. Furthermore, using clinical retrospective observational data, we found that mechanostimulation significantly promotes erectile function in patients irrespective of PDE5i use. Our studies lay the groundwork for exploring the mechano-YAP/TAZ-adrenomedullin axis as a potential target in the treatment of ED.

Summary: The commonly utilized phosphodiesterase type 5 inhibitors do not lead to satisfactory penile erection after radical prostatectomy mainly because of insufficient nitric oxide drive from the damaged cavernous nerves. The aim of this study was to assess the efficacy and mechanisms of icariin in combination with daily sildenafil on neurogenic erectile dysfunction and penile atrophy in a rat model of bilateral cavernous nerves injury. Sixty male Sprague–Dawley rats injected with 5‐ethynyl‐2‐deoxyuridine (50 mg/kg) at postnatal day 1 for the purpose of tracking endogenous stem cells in penis. Forty‐eight rats of bilateral cavernous nerves injury were randomized equally into gavage feeding of vehicle, sildenafil (10 mg/kg), icariin (1.5 mg/kg) and sildenafil + icariin, respectively. Twelve sham‐operated rats served as control. The intracavernous pressure and mean arterial pressure was measured and mid‐penile cross sections were histologically examined 5 weeks after surgery. Western blotting of cavernous tissue protein was also performed. Animals treated with sildenafil + icariin had significantly higher mean intracavernous pressure/mean arterial pressure ratio relative to other rats with bilateral cavernous nerves injury (p < 0.05). The circumference and mean cross‐sectional area of the paired corpus cavernosum were effectively preserved in the sildenafil + icariin. Treatment with sildenafil + icariin significantly increased the cavernous cyclic guanosine monophosphate concentration compared with the icariin group (p < 0.05). In addition, the numbers of neuronal nitric oxide synthase‐positive nerves and 5‐ethynyl‐2‐deoxyuridine‐positive cells co‐expressing S100 in the icariin‐treated groups were greater compared with the bilateral cavernous nerves injury control group (p < 0.05). These data suggest that the combined use of icariin and daily sildenafil holds promise as a potential therapy for neurogenic erectile dysfunction in the future. The underlying mechanisms appears to involve two aspects: (i) icariin promotes differentiation of endogenous stem cells to Schwann cells, which help to repair the damaged neural pathway for erection; (ii) on this basis, sildenafil can further improve penile engorgement through the cyclic guanosine monophosphate‐dependent smooth muscle relaxation.