Vacuum erection device (VED), used to treat radical prostatectomy (RP)-associated erectile dysfunction, has attracted considerable attention. However, the optimal negative pressure remains to be determined. This investigation explored the optimal pressure for VED therapy in penile rehabilitation. Thirty-six 9-week-old male rats were randomly divided into six groups: control groups (sham group, bilateral cavernous nerve crush [BCNC] group) and VED therapy groups (−200 mmHg group, −300 mmHg group, −400 mmHg group, −500 mmHg group). BCNC group and VED therapy groups underwent BCNC surgery. Intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio was calculated to assess erectile function. Masson’s trichrome (MT) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and real-time polymerase chain reaction (RT-PCR) were performed to explore cellular and molecular changes of the penis. Compared to the BCNC group, ICP/MAP ratios in all VED treatment groups were improved significantly (all P < 0.05), but there were no statistically significant differences among VED therapy groups. With increased pressure, complications gradually emerged and increased in frequency. Expression of molecular indicators, such as endothelial nitric oxide synthase (eNOS) and alpha-smooth muscle actin (α-SMA), increased after VED therapy, and hypoxia-inducible factor 1α (HIF-1α) and transforming growth factor beta (TGF-β) decreased. In addition, VED therapy improved the outcomes of MT and TUNEL assay. This investigation demonstrated a pressure of −200 mmHg in a rat model is optimal for VED therapy for penile rehabilitation after RP. No further benefits were observed with increased pressure, despite an increase in complications.
Prostate cancer (PCa) is the most commonly diagnosed solid cancer in men and the third leading cause of cancer-related death in developed countries. Although the incidence of PCa is high, likely due in part to the improvement of detection and therapeutic modalities, the 5-year survival rates have improved significantly and are close to 100% in localized PCa. Despite these improvements, several maladies associated with radical prostatectomy (RP) have also emerged, which severely impact the quality of life of these patients and may include urinary incontinence and erectile dysfunction (ED). With the promotion of nerve-sparing techniques, urologists see the clinical importance of recovering erectile function (EF) of patients with PCa after RP. However, several investigations have revealed that ED after RP is a complicated pathological process involving a variety of underlying mechanisms, which include neuropraxia, ischemic and hypoxic nerve insults, fibrotic remodeling, and apoptosis of the cavernous smooth muscle.
Penile rehabilitation, which provides significant improvement in EF after RP, has attracted considerable attention and is defined as the use of medicine or device to stimulate recovery of EF after RP.Currently, the primary approaches of penile rehabilitation include oral phosphodiesterase type-5 inhibitors, vacuum erection device (VED), intracorporeal injection of vasoactive agents or intra-urethral suppository therapy, and a combinational approach of these therapies. VED works through negative pressure to distend the corporal sinusoids, thereby increasing blood inflow to the penis. Multiple studies have confirmed its value in preserving the penile size and incomplete facilitation of EF.Moreover, regarding the benefits from the rat model, bilateral cavernous nerve crush (BCNC) simulating ED after RP in humans, and our previous patent, the rat-specific VED, our team have verified the effects of VED therapy in antihypoxic, antiapoptotic, and antifibrotic mechanism. Soon after, Linet al.also showed improvement of intracavernosal blood oxygen saturation (SO2) using VED in rats after BCNC.
Although the positive effects of VED are well documented, a uniform therapeutic regimen remains to be determined. Most of the existing approaches are based on experience, so there is a lack of evidence-based guidance for the use of VED in penile rehabilitation after RP. Current suggestions for devices used to improve EF after RP are negative pressure settings that range from −150 mmHg to −200 mmHg. Nevertheless, the impact of other negative pressure values to treat ED remains unclear. Moreover, in consideration of the widespread use of VED, it is possible that patients are surrounded by unsafe and unqualified vacuum devices that may pose danger to the user. Therefore, it is crucial to understand the influences of these different negative pressures.
Based on BCNC rat models imitating ED after RP in humans, the purpose of this investigation was to elucidate the effects of different negative pressures on the penis, which would provide scientific evidence for the clinical application of VED therapy on penile rehabilitation.
ED, a common complication associated with RP, severely affects the quality of life of patients with PCa. VED therapy, based on its reported ability to improve EF,has attracted considerable attention and is now the second leading treatment modality in penile rehabilitation.However, because of a general lack of mechanistic insight on the effects of VED and the unified guidance for its application in penile rehabilitation, its clinical utility has remained limited. Therefore, our study aimed to quantify the use of VED and was conducted to show the effects of different negative pressures on the penis with a detailed exploration of mechanisms associated with a function in the BCNC rat model.
Indeed, there are many anatomical and histological differences between the human and rat penises, and owing to the limitations of clinical research, the exploration of the corresponding mechanism of VED in penile rehabilitation after RP is inevitably hindered. Therefore, our laboratory has previously established a rat-specific VED, which accurately simulated the pressure created by VEDs used in humans. In addition, we had also suggested the possible mechanism of VED therapy in penile rehabilitation in the following research based on this device. The rat VED protocol employed herein fully simulates the clinical human VED regimen in penile rehabilitation. As indirect evidence for clinical uses, results from this investigation suggest that different effects of negative pressure exist, and if an excessive pressure should be used, the penile tissue may be harmed at the deeper level. Of course, we need to point out that there may be some differences between animals and humans, and further clinical research is needed to confirm our conclusion.
As the outcomes shown in the present investigation, the ICP/MAP ratios were effectively elevated in BCNC with VED therapy groups, which presented an improvement in EF. This outcome is consistent with results reported previously and further supports results obtained from clinical trials. In addition to the ICP/MAP ratios, the exploration of molecular indicators related to penile rehabilitation was also executed to verify this change. Our previous study indicated that VED facilitated penile rehabilitation based on antihypoxic, antiapoptotic, and antifibrotic mechanisms, which were also confirmed herein. The levels of indicators, such as eNOS and α-SMA, in all VED therapy groups, exhibited increasing trends when compared with those in the BCNC group. Moreover, HIF-1α and TGF-β, contributors to the formation of apoptosis and fibrosis, were attenuated in VED therapy groups. Furthermore, Lin et al. also suggested similar outcomes, in which VED therapy can effectively preserve penile size in rats with BCNC injury relating to antihypoxia by increasing cavernous blood SO2. The signal pathway associated with the molecular indicator HIF-1α is the key to antihypoxic mechanism. Although this point has been verified in our outcomes and that in Lin et al.'s study, antihypoxia is an extremely complicated process, and more detailed information on this signal pathway is needed in further studies. In addition, the effectiveness of VED therapy in improving diseases related to penile fibrosis, such as Peyronie’s disease, is also worthy of our attention, which has been related to antiapoptosis, antifibrosis, and smooth muscle preservation. Among these mechanisms, change in TGF-β expression is important in penile fibrosis, which could bind serine and threonine kinase receptors activating Smad transcription factors, and the latter is essential in the pathogenesis of fibrotic disorder. Similar antifibrotic effects have also been mentioned in Tsambarli’s study.These studies are basically consistent with our research. Subject to the different focuses in these studies and ours, our study focuses on the choice of negative pressure, and these signal pathways related to TGF-β and Smad transcription factors have not been explored in depth in our research, showing us a good idea to explore the detailed mechanism of VED therapy.
There are some limitations to the present investigation. Specifically, although numerous preclinical and clinical trials have supported our understanding of the positive effects of VED in preserving penile size, whether excessive negative pressure provides similar benefits or even worse drawbacks remains unclear and should be further confirmed in the future studies. In addition, although our study indicates that the effects of VED therapy are related to antihypoxic, antiapoptotic, and antifibrotic mechanisms, the deep related molecular signaling pathways are still unclear, and further studies are needed. Moreover, the influences of excessive negative pressure on the cavernous blood SO2– an indicator further illuminating the detailed mechanism related to penile rehabilitation with the VED – and penile vein occlusion function should also be explored in subsequent studies.
The present study shows that a pressure of −200 mmHg seems to be the optimal choice in VED therapy for penile rehabilitation based on the rat model. No additional benefits that could help preserve the EF or improve the penile tissue structure after RP can be obtained from excessive negative pressure, except for increased detrimental side effects. In addition, based on the advantages of VED therapy, multiple therapies combined with VED have emerged and achieved more remarkable successes, and the corresponding complex mechanisms are also worth our attention.