We have shown that SHH protein is decreased following CN injury and that SHH inhibition is able to upregulate BMP4 in the corpora cavernosa. The decrease in SHH protein, accompanied by increased apoptosis, suggests that the mechanism described above may be active in the penis following CN injury. Bmp4 expression was unaltered with CN injury. However, Bmp4 plays a role in and is regulated by several pathways that do not involve Shh, and the protein levels of BMP4 may be different than the RNA expression levels with CN injury, as is the case with SHH.
Since SHH treatment is able to prevent CN injury-induced apoptosis in the corpora cavernosa, it is likely that SHH inhibition plays a key role in apoptosis induction in the penis following denervation.
However, further experiments are required in order to identify the mechanism of how this process occurs.
A possible mechanism of how SHH maintains penile architecture involves VEGFA. The active form of SHH protein and its receptor PTCH1 are localized in Schwann cells and in veins adjacent to the nerves in the penis. We hypothesize that SHH in Schwann cells of penile nerves regulate homeostasis of adjacent vascular structures through induction of VEGFA.