Presentation Authors: Shawn Choe, Elizabeth Kalmanek, Chicago, IL, Daniel Harrington, Houston, TX, Samuel Stupp, Kevin McVary, Carol Podlasek*, Chicago, IL
Introduction: Erectile dysfunction (ED) occurs in up to 86% of prostatectomy and 75% of diabetic patients and has a high impact on men&[prime]s health and quality of life. Current treatments are ineffective in the difficult to treat prostatectomy (16-82%) and diabetic (56-59%) patients due to injury to the cavernous nerve (CN). With denervation corporal cavernosal smooth muscle (SM) undergoes apoptosis and the penis becomes fibrotic, thus altering the corpora cavernosal architecture. In order to devise novel ED therapies, prevention of corpora cavernosal remodeling is essential. A critical regulator of penile architecture is the sonic hedgehog (SHH) pathway, which establishes and maintains penile SM and is critical for SM regeneration after CN injury. SM apoptosis can take place via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway. We examine parallel mechanisms of how apoptosis occurs in response to SHH inhibition and in a CN injury rat model in order to identify significant points for intervention and ED therapy development.
Methods: Immunohistochemical analysis for caspase 3 cleaved, -8 and -9 (pro and active forms) were performed on corpora cavernosal tissue from adult Sprague Dawley rats that underwent SHH inhibition with 5E1 in the corpora cavernosa and in the PG, and after CN crush with SHH treatment for 9 days (n=30).
Results: SHH inhibition in the corpora cavernosa or in the PG induces apoptosis by the same mechanism as occurs in the rat after CN injury (intrinsic-caspase 9 dependent). SHH treatment after CN injury suppresses caspase 9 induction, which occurs first in a broad layer under the tunica. Little to no caspase 8 was observed under the tunica. Caspase 8 was present at low abundance in the lining of corpora cavernosal sinuses and between the sinuses after CN injury, and SHH treatment suppressed the caspase 8 response.
Conclusions: Inhibition of SHH pathway signalling in the penis and PG/CN induces an apopototic response in the penis by the same mechanism that occurs with CN injury (intrinsic-caspase 9 dependent), further strengthening the validity of our model. SHH treatment by peptide amphiphile after CN injury, suppresses primarily the caspase 9 apoptotic pathway, but also caspase 8 dependent mechanisms, supporting SHH as a key regulator of erectile function. Understanding how apoptosis takes places after CN injury and in response to SHH treatment is critical for translation to ED patients.
Source of Funding: NIH/NIDDK DK101536