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. Author manuscript; available in PMC: 2009 Aug 4.
Published in final edited form as: J Sex Med. 2009 Mar;6(Suppl 3):334–339. doi: 10.1111/j.1743-6109.2008.01192.x

Sonic hedgehog, Apoptosis and the Penis

Carol A Podlasek 1
PMCID: PMC2720523  NIHMSID: NIHMS115455  PMID: 19267857

Abstract

Introduction

Smooth muscle apoptosis in the penis is common in prostatectomy patients and animal models of erectile dysfunction (ED). A critical regulator of smooth muscle apoptosis in the penis is the secreted protein Sonic hedgehog (SHH). Since SHH protein treatment of the penis prevents cavernous nerve (CN) injury induced apoptosis, SHH has the potential to treat post-prostatectomy apoptosis. However little is known about how SHH signaling is regulated in the adult penis.

Aim

The goal of this review is to examine what is known about SHH signaling in the penis, to offer insight as to how SHH inhibition induces apoptosis in penile smooth muscle, and to define the role of the SHH pathway in maintaining CN integrity.

Methods

Information presented in this review was derived from a literature search using the National Library of Medicine PubMed Services. Search terms included SHH, apoptosis, smooth muscle, penis, ED, pelvic ganglia, corpora cavernosa, CN, regeneration, Schwann cell, neural activity and transport.

Results

In this review we have discussed the role of the CN in regulation of SHH abundance and apoptosis induction in the penis and have examined the function and localization of SHH signaling in the CN.

Conclusion

There is substantial potential to develop SHH for delivery to the penis of prostatectomy patients at the time of surgery in order to prevent apoptosis induction and long term ED development. Studies are in progress which will identify if SHH may be used as a regenerative therapy to speed CN regeneration.

Erectile Dysfunction

Forty to seventy percent of prostate cancer patients treated by radiotherapy1–2 and 30–87% of patients treated by radical prostatectomy experience ED2–5. Although potency improves with time post prostatectomy6, ED is common 5 years following surgery7. There is a greater concern for quality of life in prostatectomy populations due to improved treatment strategies and younger age of diagnosis. Survey studies of men electing treatment for localized prostate cancer reveal quality of life is a primary concern in 45% of participants8. Radical prostatectomy is performed on over 60,000 men each year and is the most common treatment for prostate cancer9–10. The current ten-year survival rate is estimated to be 92%, suggesting that men will experience the side effects of treatment for long periods of time10. Since oral therapy with PDE5 inhibitors are ineffective in 29–86% of prostatectomy patients who experience ED11–12, novel therapeutic approaches to treat ED are needed.

Smooth muscle apoptosis is a cause of ED

Significantly increased apoptosis of penile smooth muscle is a common etiology in both animal models and human patients with ED13–20 and in patients that do not respond to phosphodiesterase type 5 (PDE5) inhibitors, smooth muscle cell atrophy is abundant21. These results suggest that abundant apoptosis observed in penile smooth muscle when the CN is cut is a major contributing factor to ED development and that innervation of the penis by the CN plays an important role in maintaining normal penile morphology necessary for erection to occur. When SHH function is inhibited in normal Sprague Dawley rats, smooth muscle apoptosis and ED occur, confirming that smooth muscle apoptosis in the penis is a cause of ED22,15. Current treatment strategies for ED are designed to increase smooth muscle relaxation; however, these strategies become ineffective once smooth muscle apoptosis occurs due to lack of penile innervation23. If penile apoptosis could be prevented following prostatectomy while the CN regenerates, then resumption of normal erectile function would occur more quickly, and fibrosis would be prevented as would long term ED development. Thus in order to prevent penile apoptosis after CN injury/prostatectomy, it is critical to develop therapies that will aid/speed the process of CN regeneration and thus prevent smooth muscle apoptosis.

SHH pathway

Sonic hedgehog (SHH) is a secreted protein that is expressed at sites of mesenchymal-epithelial interaction in many organs. SHH orchestrates tissue sculpting by regulating cellular proliferation, apoptosis, differentiation and cell survival, via manipulation of its targets transcription. SHH can either act directly or by induction of secondary signals including, its receptor patched (PTCH1), smoothened (SMO), hedgehog-interacting-protein (HIP), HOX, bone morphogenetic protein-4 (BMP4), vascular endothelial growth factor (VEGF), nitric oxide synthase (NOS), fibroblast growth factor (FGF), and WNT.

Little is known about SHH signal transduction in the adult penis and pelvic ganglia, however SHH signaling has been well established in other organs during embryogenesis. The SHH signal is transduced through the interplay between PTCH1 and SMO. PTCH1 is a 12-transmembrane protein24–27 that functions as a receptor for SHH. PTCH1 binds to SHH but does not transduce the intracellular signal. SMO, a 7-transmembrane protein that forms a receptor complex with PTCH127, does not bind to SHH but transduces the SHH signal through activation of the GLI family of transcription factors. In the absence of SHH protein bound to PTCH1, PTCH1 represses down stream targets of SHH signaling by inhibiting the activity of SMO at the substoichiometrical level28. When SHH protein binds to PTCH1, this relieves the repression of PTCH1 on SMO and allows transcription of SHH’s down stream targets29–34 (Figure 1). A transcriptional target of SHH signaling is PTCH1 itself. When SHH binds to PTCH1, PTCH1 expression is increased35. By increasing the level of PTCH1 protein in responding cells, SHH signaling attenuates its own activity in a negative feedback loop36. Thus when SHH protein is abundant so is PTCH1 and when SHH protein is decreased, PTCH1 protein is similarly decreased. We have shown in animal models of neuropathy and ED that Ptch1 signaling is altered in parallel with Shh expression37, 15.

Figure 1.

Figure 1

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Diagram of the pathway of SHH signal transduction.

SHH regulates penile development and postnatal differentiation

During embryogenesis, SHH is expressed in the urogenital sinus, the tissue from which the penis and prostate derive38. Shh expression is necessary for both genital tubercle outgrowth and differentiation39 and external genitalia are absent in mice with a targeted deletion of Shh40. Shh is expressed through out the entire period of postnatal differentiation of the penis, with increased expression occurring at puberty and the highest expression evident in the adult penis, suggesting continued function in the adult. SHH is localized primarily in the smooth muscle lining the corpora cavernosal sinuses, but is also present in a proliferative region under the tunica, the nerves and urethra. It has been shown in SHH inhibition studies in the penis that SHH is essential to establish and maintain the sinusoid morphology of the penis22.

Why is SHH important in the adult penis?

SHH is a critical regulator of penile smooth muscle. When SHH function is inhibited in adult rat penis using the 5E1 inhibitor (disrupts binding of SHH to PTCH141–42), a 12-fold increase in apoptosis occurs. Electron microscopy and dual TUNEL analysis/α-actin immunohistochemical analysis show that apoptosis occurs primarily in penile smooth muscle15. The morphological changes induced by SHH inhibition are so severe that ED occurs, as measured by a 4-fold decrease in ICP/blood pressure (p-value=0.009)22. The morphology changes caused by SHH inhibition are reversible when SHH inhibition is removed15. These results show that inhibition of SHH function in vivo causes ED due to extensive smooth muscle apoptosis.

SHH protein treatment of the corpora cavernosa suppresses CN injury induced apoptosis15. When SHH protein is delivered to the penis via Affi-Gel beads at the same time as bilateral CN injury is performed in adult Sprague Dawley rats, apoptosis was suppressed 1.25-fold after 4 days of SHH treatment (p-value=0.02)15. When double the concentration of SHH protein was applied, apoptosis was suppressed in a larger region surrounding the bead vehicles and was further reduced 2.5-fold (p-value=3.39E−05). At 8 days post CN injury, apoptosis was suppressed 3-fold in the presence of SHH protein (p-value=9.03E−05). These results show that SHH has significant potential for clinical application to suppress apoptosis post prostatectomy. Thus is would be highly beneficial to have a better understanding of the mechanisms which regulate SHH abundance in the penis.

How is SHH signaling regulated in the adult penis?

Although SHH regulation of apoptosis in the penis is well established15, how SHH itself is regulated is not well defined. Since SHH protein is decreased at the same time as apoptosis is increased in both the BB/WOR diabetic37 and CN injured Sprague Dawley15 rat models of neuropathy, this suggests that neural input plays a role in regulation of SHH abundance in the penis. There are three potential mechanisms of how neural input may regulate SHH abundance and apoptosis induction in the penis. These are: 1.) Neural activity may regulate SHH abundance, 2.) Transport of a trophic factor from the pelvic ganglia to the penis may regulate SHH in the penis, and 3.) SHH protein may be transported from the pelvic ganglia to the penis via the CN. We have examined each of these potential mechanisms by using gel foam to deliver lidocaine or colchicine to the CN and examine SHH abundance and apoptosis in the penis and by performing bilateral CN tie and examining the CN for potential buildup of SHH protein near the tie. We found that inhibition of neural activity and transport with 2% lidocaine for two days (an inhibitor of nerve conduction and axonal transport43–44) in adult Sprague Dawley rats caused a 1.3-fold decrease in SHH protein (p-value=0.01) and a 1.6-fold increase in apoptosis (p-value=0.049) in the penis45. Similar experiments performed using 5 mM colchicine treatment for one day (inhibits the polymerization of tubulin and prevents biological processes where microtubules are involved, including blockade of anterograde and retrograde transport46–50) caused a 1.2-fold decrease in SHH protein (p-value=0.006) and a 1.8-fold increase in apoptosis (p-value=0.015) in the penis45. These findings are significant because they show that both neural activity and transport are critical for regulation of SHH abundance and apoptosis induction in the penis.

In order to test if SHH protein undergoes anterograde transport from the pelvic ganglia to the penis via the CN, a silk tie was placed around the CN bilaterally in adult Sprague-Dawley rats. Immunohistochemical analysis of the CN and pelvic ganglia assayed for SHH protein show that SHH protein does not build up on either side of the tie, indicating that SHH is not transported by the CN45. However, neuronal nitric oxide synthase (NOSI) was observed to build up on the ganglia side of the tie, indicating that protein build up would be visualized if present. Thus SHH protein is not transported from the CN to the penis. SHH was abundant in Schwann cells of the CN, which were recruited to the site of tie placement to aid in the process of axonal repair45. Both myelinating and non-myelinating Schwann cells exist in peripheral nerves such as the CN51–53. Upon injury, they help to phagocytize the damaged end of an axon and then proliferate rapidly to form a scaffold to guide regenerating axons. Thus the presence of SHH in Schwann cells suggests a role for the SHH pathway in maintaining CN integrity. This is supported by previous observations in which SHH inhibition in the pelvic ganglia decreased SHH protein abundance and increased apoptosis in the penis despite SHH protein not being transported by the CN45. These studies suggest that SHH plays a role in regulating CN integrity and that CN activity and a trophic factor from the CN are at least partially responsible for maintaining SHH abundance and normal morphology in the penis.

The SHH pathway and CN regeneration

After CN injury, profound changes in neurotrophic factor signaling occur in the CN. Schwann cells crucially contribute to successful regeneration by mechanical and paracrine influences in the injured nerve. Schwann cells have been successfully used to promote CN regeneration54 and Schwann cell seeded nerve guidance tubes have been used to restore erections and promote regeneration after bilateral CN cut in rats55. The addition of neurotrophic factors, extra cellular matrix components and Schwann cells have been shown to promote regeneration56–59. Several molecules have been described to have neurotrophic effects in the penis including VEGF60–61, which is a target of SHH signaling62. In normal adult rats, SHH is abundant in NOSI positive neurons of the pelvic ganglia that innervate the penis and in Schwann cells of the CN45. These results suggest that SHH may be a factor of the Schwann cells that is required for CN regeneration and that SHH may play a regulatory role in regeneration after CN injury.

Conclusions

Since SHH is a critical regulator of smooth muscle apoptosis in the penis that is able to prevent CN injury induced apoptosis in rats, there is substantial potential to develop SHH for delivery in a localized manner to the penis of prostatectomy patients at the time of surgery in order to prevent apoptosis induction and long term ED development as the CN regenerates. Studies are in progress which will identify whether SHH may have application as a regenerative therapy to speed the process of peripheral nerve regeneration.

Acknowledgments

Grant Sponsor-National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, Grant numbers: DK068507.

Footnotes

Conflict of Interest: None

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