Delayed Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates Impaired Penile Hemodynamics in Rats Subjected to Pelvic Neurovascular Injury

Abstract

Background: Erectile dysfunction (ED) caused by pelvic neurovascular injury (PNVI) is often refractory to treatment. In many cases erectogenic therapy is administered in a delayed fashion. Aims: To evaluate penile hemodynamic effects and histological changes associated with delayed low-intensity extracorporeal shock wave therapy (Li-ESWT) after PNVI ED in a rat model. We visualized images using immunofluorescence and 3-dimensional imaging of solvent cleared organs (3DISCO), a novel imaging technique. Methods: 32 Sprague-Dawley male rats aged 12 weeks-old were divided equally into four groups: sham surgery as normal controls (NC), PNVI controls (PC), PNVI with very-low-energy Li-ESWT (PVL), and PNVI with low-energy Li-ESWT (PL) group. Bilateral cavernous nerve (CN) crush and internal pudendal bundle (IPB) ligation were performed in the PNVI groups. Li-ESWT was administered twice a week for four weeks in the PL and PVL groups starting 4 weeks after PNVI. Outcomes: Intracavernous pressure (ICP) studies (normalized to Mean Arterial Pressure, MAP) were conducted in all subject animals. After testing, tissue was harvested for immunofluorescence staining and 3DISCO. Results: Mean ICP/MAP was lower in PC compared to NC animals (0.37 ± 0.03 vs 0.91 ± 0.03, respectively, p=0.001). The ICP/MAP ratio was significantly higher in PVL and PL animals (0.66 ± 0.07 and 0.82 ± 0.05, respectively) compared to PC animals (p=0.002 and 0.001, respectively). Detailed microstructures and trajectories of nerves and vessels were identified with immunofluorescence and 3DISCO. The PC group had lower density of nerves, axons, nNOS positive nerves, and Schwann cells in the dorsal penis. Animals in the PL group had significantly higher expression of all of these markers compared to PC animals. Clinical Implications: Li-EWST may have utility in the management of severe ED related to PNVI from severe pelvic injury or radical pelvic surgeries, even when administered in a delayed fashion. Strengths and Limitations: This study of a severe ED phenotype involved treatment administered in a delayed fashion, which is more consistent with how therapy would likely be delivered in a real world clinical context. Moreover, since the treatment commenced 4 weeks after injury when nerve and tissue atrophy have already occurred, the results imply that Li-ESWT can be used for regenerative therapy. Additional studies on dose optimization and treatment interval are required to inform the design of human clinical trials Conclusions: Li-ESWT ameliorates the negative functional and histological effects of severe pelvic neurovascular injury in a rat model system. 3DISCO provided high-resolution images of neuroanatomy and neural regeneration.

Efficacy of penile low-intensity shockwave treatment for erectile dysfunction: correlation with the severity of cavernous artery disease

“… 12 21 It has been shown that this Li-ESWT energy level induces cell membrane modifications and funtional changes such as the stimulation of mechanosensor, induction of neangiogenesis, recruitment, improvement, and activation of endothelial progenitor cells, nerve regeneration, erectile tissue remodeling through an increase in the muscle/collagen ratio and by reducing inflammatory and cellular stress responses. 21 22 23 24 25 26 27 28 29 30 31 32 To date, there are no data regarding the effects of Li-ESWT on patients with ED with or without atherosclerotic cavernous artery disease. The results of our study, although limited to a relatively small cohort, show that patients with mild ED and without cavernous artery disease are younger and have a better and longer lasting response to treatment.…”

An update on the current status and future prospects of erectile dysfunction following radical prostatectomy

“…Further explorations of LI-ESWT for ED and 3dimensional imaging of solvent cleared organs for assessment of microstructural changes are warranted. 144 The use of LI-ESWT was as safe as oral PDE5is. So, LI-ESWT could be an alternative, especially if there are contraindications to PDE5i.…”

“…143 Delayed application of LI-ESWT to the penis and pelvis was associated with restoration of penile hemodynamics in a rodent model of severe pelvic neurovascular injury. 144 These effects seem to be mediated by LI-ESWT-enhanced angiogenesis, activation of Schwann cells, and facilitation of nerve regeneration. Threedimensional imaging of solvent cleared organs provided highresolution images of unsectioned CN and major pelvic ganglion and demonstrated superior neuronal integrity in animals treated with LI-ESWT.…”

“…Threedimensional imaging of solvent cleared organs provided highresolution images of unsectioned CN and major pelvic ganglion and demonstrated superior neuronal integrity in animals treated with LI-ESWT. 144…”

Revisiting the Regenerative Therapeutic Advances Towards Erectile Dysfunction

“…In diabetic ED rats, LI-ESWT seems to downregulate the receptor of advanced glycation end products (RAGE) and upregulate factors such VEGF, nNOS, and α-SMA, leading to increased content of smooth muscles, endothelial cells, and ECM [27]. In a rat model of pelvic neurovascular injury (PNVI)-induced ED, LI-ESWT ameliorates impaired penile hemodynamics by improving nerve cell content with an increase in nNOS-positive nerves, Schwann cells, and axons in dorsal penis [28].…”