Regulation of Cavernous Nerve Injury-induced Apoptosis by Sonic Hedgehog

Overview

Journal Biol Reprod

Publisher Oxford University Press

Specialty Reproductive Medicine

Date 2006 Sep 22

PMID 16988214

Citations 37

Authors

Carol A Podlasek

Cynthia L Meroz

Yi Tang

Kevin E McKenna

Kevin T McVary

Affiliations

Soon will be listed here.

Abstract

Thirty to eighty-seven percent of patients treated by radical prostatectomy experience erectile dysfunction (ED). The reduced efficacy of treatments in this population makes novel therapeutic approaches to treat ED essential. We propose that abundant apoptosis observed in penile smooth muscle when the cavernous nerve (CN) is cut (mimicking the neural injury which can result from prostatectomy) is a major contributing factor to ED development. We hypothesize that decreased Sonic hedgehog (SHH) signaling is a cause of ED in neurological models of impotence by increasing apoptosis in penile smooth muscle. We examined this hypothesis in a bilateral CN injury model of ED. We found that the active form of SHH protein was significantly decreased 1.2-fold following CN injury, that SHH inhibition causes a 12-fold increase in smooth muscle apoptosis in the penis, and that SHH treatment at the time of CN injury was able to decrease CN injury-induced apoptosis (1-3-fold) in a dose-dependent manner. These results show that SHH stabilizes the alterations of the corpora cavernosal smooth muscle following nerve injury.

Citing Articles

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BMP4 and GREM1 are targets of SHH signaling and downstream regulators of collagen in the penis.

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References

Way K, REID J . The effects of diabetes on nitric oxide-mediated responses in rat corpus cavernosum. Eur J Pharmacol. 1999; 376(1-2):73-82. DOI: 10.1016/s0014-2999(99)00347-7. View

Goodrich L, Johnson R, Milenkovic L, McMahon J, Scott M . Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog. Genes Dev. 1996; 10(3):301-12. DOI: 10.1101/gad.10.3.301. View

Mukouyama Y, Gerber H, Ferrara N, Gu C, Anderson D . Peripheral nerve-derived VEGF promotes arterial differentiation via neuropilin 1-mediated positive feedback. Development. 2005; 132(5):941-52. DOI: 10.1242/dev.01675. View

Wang J, McKenna K, Lee C . Determination of prostatic secretion in rats: effect of neurotransmitters and testosterone. Prostate. 1991; 18(4):289-301. DOI: 10.1002/pros.2990180403. View

Burchardt T, Burchardt M, Karden J, Buttyan R, Shabsigh A, de la Taille A . Reduction of endothelial and smooth muscle density in the corpora cavernosa of the streptozotocin induced diabetic rat. J Urol. 2000; 164(5):1807-11. View

Pola R, Ling L, Aprahamian T, Barban E, Bosch-Marce M, Curry C . Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia. Circulation. 2003; 108(4):479-85. DOI: 10.1161/01.CIR.0000080338.60981.FA. View

Zhang Z, Song Y, Zhao X, Zhang X, Fermin C, Chen Y . Rescue of cleft palate in Msx1-deficient mice by transgenic Bmp4 reveals a network of BMP and Shh signaling in the regulation of mammalian palatogenesis. Development. 2002; 129(17):4135-46. DOI: 10.1242/dev.129.17.4135. View

Penson D, McLerran D, Feng Z, Li L, Albertsen P, Gilliland F . 5-year urinary and sexual outcomes after radical prostatectomy: results from the prostate cancer outcomes study. J Urol. 2005; 173(5):1701-5. DOI: 10.1097/01.ju.0000154637.38262.3a. View

Guerrero I, Ruiz i Altaba A . Development. Longing for ligand: hedgehog, patched, and cell death. Science. 2003; 301(5634):774-6. DOI: 10.1126/science.1088625. View

10.

Perriton C, Powles N, Chiang C, Maconochie M, Cohn M . Sonic hedgehog signaling from the urethral epithelium controls external genital development. Dev Biol. 2002; 247(1):26-46. DOI: 10.1006/dbio.2002.0668. View

11.

Korfage I, Essink-Bot M, Borsboom G, Madalinska J, Kirkels W, Habbema J . Five-year follow-up of health-related quality of life after primary treatment of localized prostate cancer. Int J Cancer. 2005; 116(2):291-6. DOI: 10.1002/ijc.21043. View

12.

Kalsi J, Ralph D, Thomas P, Bellringer J, Minhas S, Kell P . A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide. J Sex Med. 2006; 2(1):53-7. DOI: 10.1111/j.1743-6109.2005.20105.x. View

13.

Kusano K, Pola R, Murayama T, Curry C, Kawamoto A, Iwakura A . Sonic hedgehog myocardial gene therapy: tissue repair through transient reconstitution of embryonic signaling. Nat Med. 2005; 11(11):1197-204. DOI: 10.1038/nm1313. View

14.

Cartledge J, Eardley I, Morrison J . Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes. BJU Int. 2001; 87(4):394-401. DOI: 10.1046/j.1464-410x.2001.00065.x. View

15.

Ma X, Sheng T, Zhang Y, Zhang X, He J, Huang S . Hedgehog signaling is activated in subsets of esophageal cancers. Int J Cancer. 2005; 118(1):139-48. DOI: 10.1002/ijc.21295. View

16.

Hetts S . To die or not to die: an overview of apoptosis and its role in disease. JAMA. 1998; 279(4):300-7. DOI: 10.1001/jama.279.4.300. View

17.

Haraguchi R, Mo R, Hui C, MOTOYAMA J, Makino S, Shiroishi T . Unique functions of Sonic hedgehog signaling during external genitalia development. Development. 2001; 128(21):4241-50. DOI: 10.1242/dev.128.21.4241. View

18.

User H, Hairston J, Zelner D, McKenna K, McVary K . Penile weight and cell subtype specific changes in a post-radical prostatectomy model of erectile dysfunction. J Urol. 2003; 169(3):1175-9. DOI: 10.1097/01.ju.0000048974.47461.50. View

19.

Bastida M, Delgado M, Wang B, Fallon J, Fernandez-Teran M, Ros M . Levels of Gli3 repressor correlate with Bmp4 expression and apoptosis during limb development. Dev Dyn. 2004; 231(1):148-60. DOI: 10.1002/dvdy.20121. View

20.

Kendirci M, Hellstrom W . Current concepts in the management of erectile dysfunction in men with prostate cancer. Clin Prostate Cancer. 2004; 3(2):87-92. DOI: 10.3816/cgc.2004.n.017. View